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Adacel

Adacel

CLINICAL PHARMACOLOGY

Background

Tetanus- Tetanus is an acute and often fatal disease caused by an extremely potent neurotoxin produced by C tetani. The toxin causes neuromuscular dysfunction, with rigidity and spasms of skeletal muscles. The muscle spasms usually involve the jaw (lockjaw) and neck and then become generalized.

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 immunization, protection generally persists for at least 10 years. (4)

Diphtheria- C 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. Both toxigenic and nontoxigenic strains of C diphtheriae can cause disease, but only strains that produce toxin can cause severe manifestations such as myocarditis and neuritis. Toxigenic strains are more often associated with severe or fatal respiratory infections than with cutaneous infections.

Complete immunization significantly reduces the risk of developing diphtheria and immunized persons who develop disease have milder illness.

Immunization with diphtheria toxoid does not, however, eliminate carriage of C diphtheriae in the pharynx, nose, or on the skin. Following immunization, protection lasts at least 10 years. (4)

Pertussis- Pertussis (whooping cough) is a disease of the respiratory tract, most often caused by B pertussis. This gram-negative coccobacillus produces a variety of biologically active components, though their role in pathogenesis is not clearly defined.

Mechanism of Action

Protection against disease attributable to C tetani is due to the development of neutralizing antibodies to tetanus toxin. A serum antitoxin level of ≥ 0.1 IU/mL is considered protective, although a level of at least 0.01 IU/mL, measured by neutralization assay is considered the minimum protective level. (5) 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. (6) Levels of 1.0 IU/mL have been associated with long-term protection. (7)

The mechanism of protection from B pertussisdisease is not well understood. However, the pertussis components in Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine (i.e., detoxified PT, FHA, PRN and FIM) have been shown to prevent pertussis in infants in a clinical trial with DAPTACEL vaccine. (See Clinical Studies.)

Clinical Studies

The efficacy of the tetanus toxoid and diphtheria toxoid used in Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) 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 Sanofi Pasteur Inc., Swiftwater, PA. The primary measures of immunogenicity were (a) the percentage of participants attaining an antibody level of at least 0.1 IU/mL and (b) the percentage of participants 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 equal to or 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 (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine was inferred based on a comparison of pertussis antibody levels achieved in recipients of a single booster dose of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine with those obtained in infants after three doses of DAPTACEL vaccine. In the Sweden I Efficacy Trial, three doses of DAPTACEL vaccine were 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-confirmedB pertussis infection) was 77.9% (95% CI: 72.6%, 82.2%). (8) (9) In addition, the ability of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine to elicit a booster response to the pertussis antigens following vaccination was evaluated. The acellular pertussis formulations for Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) and DAPTACEL vaccines differ only in the amount of detoxified PT (2.5 μg in Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine versus 10 μg in DAPTACEL vaccine).

The principal immunogenicity study was a comparative, multi-center, randomized, observer-blind, controlled trial which enrolled 4,480 participants; 2,053 adolescents (11-17 years of age) and 2,427 adults (18-64 years of age). Enrollment was stratified by age to ensure adequate representation across the entire age range. Participants had not received a tetanus or diphtheria toxoid containing vaccine within the previous 5 years. After enrollment participants were randomized to receive one dose of either Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine or Td vaccine. A total of 4,461 randomized participants were vaccinated. The per-protocol immunogenicity subset included 1,270 Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine recipients and 1,026 Td vaccine recipients. Sera were obtained before and approximately 35 days after vaccination. (Blinding procedures for safety assessments are described in the ADVERSE REACTIONS section.)

Demographic characteristics were similar within age groups and between the vaccine groups. A total of 76% of the adolescents and 1.1% of the adults reported a history of receiving 5 previous doses of diphtheria-tetanus-pertussis containing vaccines. Anti-tetanus and anti-diphtheria seroprotection rates ( ≥ 0.1 IU/mL) and booster response rates were comparable between Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) and Td vaccines. (See Table 1 and Table 2.) Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine induced pertussis antibody levels that were non-inferior to those of Swedish infants who received three doses of DAPTACEL vaccine. (See Table 3.) Acceptable booster responses to each of the pertussis antigens were also demonstrated, i.e., the percentage of participants with a booster response exceeded the pre-defined lower limit. (9) (See Table 4.)

Table 1: Pre-vaccination and Post-vaccination Antibody Responses and Booster Response Rates to Tetanus Toxoid Following Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) Vaccine as Compared to Td Vaccine

Age Group
(years)
Vaccine N* Tetanus Antitoxin (IU/mL)
Pre-Vaccination 1 Month Post-Vaccination
% ≥ 0.10
(95% CI)
% ≥ 1.0
(95% CI)
% ≥ 0.10
(95% CI)
% ≥ 1.0
(95% CI)
% Booster
(95% CI)
11-17 Adacel 527 99.6
(98.6, 100.0)
44.6
(40.3, 49.0)
100.0
(99.3, 100.0)
99.6§
(98.6, 100.0)
91.7
(89.0, 93.9)
Td** 516 99.2
(98.0, 99.8)
43.8
(39.5, 48.2)
100.0
(99.3, 100.0)
99.4
(98.3, 99.9)
91.3
(88.5, 93.6)
18-64 Adacel 742-743 97.3
(95.9, 98.3)
72.9
(69.6, 76.1)
100.0
(99.5, 100.0)
97.8§
(96.5, 98.8)
63.1
(59.5, 66.6)
Td** 509 95.9
(93.8, 97.4)
70.3
(66.2, 74.3)
99.8
(98.9, 100.0)
98.2
(96.7, 99.2)
66.8
(62.5, 70.9)
*N = number of participants in the per-protocol population with available data.
Booster response is defined as: A four-fold rise in antibody concentration, if the pre-vaccination concentration was equal to or 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 cut-off value for tetanus was 2.7 IU/mL.
Seroprotection rates at ≥ 0.10 IU/mL and booster response rates to Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine were non-inferior to Td vaccine (upper limit of the 95% CI on the difference for Td vaccine minus Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine < 10%).
§Seroprotection rates at ≥ 1.0 IU/mL were not prospectively defined as a primary endpoint.
**Tetanus and Diphtheria Toxoids Adsorbed For Adult Use manufactured by Sanofi Pasteur Inc., Swiftwater, PA.

Table 2: Pre-vaccination and Post-vaccination Antibody Responses and Booster Response Rates to Diphtheria Toxoid Following Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) Vaccine as Compared to Td Vaccine

Age Group
(years)
Vaccine N* Diphtheria Antitoxin (IU/mL)
Pre-Vaccination 1 Month Post-Vaccination
% ≥ 0.10
(95% CI)
% ≥ 1.0
(95% CI)
% ≥ 0.10
(95% CI)
% ≥ 1.0
(95% CI)
% Booster
(95% CI)
11-17 Adacel 527 72.5
(68.5, 76.3)
15.7
(12.7, 19.1)
99.8
(98.9, 100.0)
98.7§
(97.3, 99.5)
95.1
(92.9, 96.8)
Td** 515-516 70.7
(66.5, 74.6)
17.3
(14.1, 20.8)
99.8
(98.9, 100.0)
98.4
(97.0, 99.3)
95.0
(92.7, 96.7)
18-64 Adacel 739-741 62.6
(59.0, 66.1)
14.3
(11.9, 17.0)
94.1
(92.1, 95.7)
78.0§
(74.8, 80.9)
87.4
(84.8, 89.7)
Td** 506-507 63.3
(59.0, 67.5)
16.0
(12.9, 19.5)
95.1
(92.8, 96.8)
79.9
(76.1, 83.3)
83.4
(79.9, 86.5)
*N = number of participants in the per-protocol population with available data.
Booster response is defined as: A four-fold rise in antibody concentration, if the pre-vaccination concentration was equal to or 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 cut-off value for diphtheria was 2.56 IU/mL.
Seroprotection rates at ≥ 0.10 IU/mL and booster response rates to Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine were non-inferior to Td vaccine (upper limit of the 95% CI on the difference for Td vaccine minus Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine < 10%).
§Seroprotection rates at ≥ 1.0 IU/mL were not prospectively defined as a primary endpoint.
**Tetanus and Diphtheria Toxoids Adsorbed For Adult Use manufactured by Sanofi Pasteur Inc., Swiftwater, PA.

Table 3: Ratio of Pertussis Antibody Geometric Mean Concentrations (GMCs)¥ Observed One Month After a Dose of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) Vaccine in Adolescents and Adults Compared with Those Observed in Infants One Month Following Vaccination at 2, 4 and 6 Months of Age in the Efficacy Trial with DAPTACEL Vaccine

  Adolescents Adults
Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) */DAPTACEL
GMC Ratio
(95% CIs)
Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) /DAPTACEL
GMC Ratio
(95% CIs)
Anti-PT 3.6
(2.8, 4.5)§
2.1
(1.6, 2.7)§
Anti-FHA 5.4
(4.5, 6.5)§
4.8
(3.9, 5.9)§
Anti-PRN 3.2
(2.5, 4.1)§
3.2
(2.3, 4.4)§
Anti-FIM 5.3
(3.9, 7.1)§
2.5
(1.8, 3.5)§
¥Antibody GMCs, measured in arbitrary ELISA units were calculated separately for infants, adolescents and adults.
*N = 524 to 526, number of adolescents in the per-protocol population with available data for Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine.
N = 80, number of infants who received DAPTACEL vaccine with available data post-dose 3 (Sweden Efficacy I).
N = 741, number of adults in the per-protocol population with available data for Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine.
§GMC following Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine was non-inferior to GMC following DAPTACEL vaccine (lower limit of 95% CI on the ratio of GMC for Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine divided by DAPTACEL vaccine > 0.67).

Table 4: Booster Response Rates to the Pertussis Antigens Observed One Month After a Dose of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) Vaccine in Adolescents and Adults

  Adolescents Adults Pre-defined
Acceptable Rates*
%
N % (95% CI) N % (95% CI)
Anti-PT 524 92.0
(89.3, 94.2)
739 84.4
(81.6, 87.0)
81.2
Anti-FHA 526 85.6
(82.3, 88.4)
739 82.7
(79.8, 85.3)
77.6
Anti-PRN 525 94.5
(92.2, 96.3)
739 93.8
(91.8, 95.4)
86.4
Anti-FIM 526 94.9
(92.6, 96.6)
739 85.9
(83.2, 88.4)
82.4
*The acceptable response rate for each antigen was defined as the lower limit of the 95% CI for the rate being no more than 10% lower than the response rate observed in previous clinical trials.
A booster response for each antigen was defined as a four-fold rise in antibody concentration if the pre-vaccination concentration was equal to or 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 cut-off values for pertussis antigens were established based on antibody data from both adolescents and adults in previous clinical trials. The cut-off values were 85 EU/mL for PT, 170 EU/mL for FHA, 115 EU/mL for PRN and 285 EU/mL for FIM.
N = number of participants in the per-protocol population with available data.

Concurrently Administered Vaccines

Hepatitis B Vaccine

The concomitant use of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine and hepatitis B (Hep B) vaccine (Recombivax HB® , 10 μg per dose using a two-dose regimen, manufactured by Merck and Co., Inc) was evaluated in a multi-center, open-labeled, randomized, controlled study that enrolled 410 adolescents, 11-14 years of age inclusive. One group received Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) and Hep B vaccines concurrently (N = 206). The other group (N = 204) received Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine at the first visit, then 4-6 weeks later received Hep B vaccine. The second dose of Hep B vaccine was given 4-6 weeks after the first dose. Serum samples were obtained prior to and 4-6 weeks after Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine administration, as well as 4-6 weeks after the 2nd dose of Hep B for all participants. No interference was observed in the immune responses to any of the vaccine antigens when Adacel and Hep B vaccines were given concurrently or separately. (9) (See DOSAGE AND ADMINISTRATION, Concomitant Vaccine Administration.)

Trivalent Inactivated Influenza Vaccine

The concomitant use of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine and trivalent inactivated influenza vaccine (TIV, Fluzone® , manufactured by Sanofi Pasteur Inc., Swiftwater, PA) was evaluated in a multi-center, open-labeled, randomized, controlled study conducted in 720 adults, 19-64 years of age inclusive. In one group, participants received Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) and TIV vaccines concurrently (N = 359). The other group received TIV at the first visit, then 4-6 weeks later received Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine (N = 361). Sera were obtained prior to and 4-6 weeks after Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) vaccine, as well as 4-6 weeks after the TIV. The immune responses were comparable for concurrent and separate administration of Adacel (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed) and TIV vaccines for diphtheria (percent of participants with seroprotective concentration ≥ 0.10 IU/mL and booster responses), tetanus (percent of participants with seroprotective concentration ≥ 0.10 IU/mL), pertussis antigens (booster responses and GMCs except lower PRN GMC in the concomitant group, lower bound of the 90% CI was 0.61 and the pre-specified criterion was ≥ 0.67) and influenza antigens (percent of participants with hemagglutination-inhibition [HI] antibody titer ≥ 1:40 IU/mL and ≥ 4-fold rise in HI titer). Although tetanus booster response rates were significantly lower in the group receiving the vaccines concurrently versus separately, greater than 98% of participants in both groups achieved seroprotective levels of ≥ 0.1 IU/mL. (9) (See DOSAGE AND ADMINISTRATION, Concomitant Vaccine Administration.)

REFERENCES

4 CDC. Diphtheria, tetanus and pertussis: recommendations for vaccine use and other preventive measures. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR-10):1-28.

5 CDC. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(RR-15):1-48.

6 FDA. Department of Health and Human Services (DHHS). Biological products bacterial vaccines and toxoids; implementation of efficacy review; proposed rule. Fed Reg 1985;50(240):51002-117.

7 Diphtheria toxoid. Tetanus toxoid. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia, PA: WB Saunders; 2004. p. 211-28, 745-81.

8 Gustafsson L, et al. A controlled trial of a two-component acellular, a five-component acellular and a whole-cell pertussis vaccine. N Engl J Med 1996;334(6):349-55.

9 Data on file at Sanofi Pasteur Limited.

Last reviewed on RxList: 1/6/2009
This monograph has been modified to include the generic and brand name in many instances.

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