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Adacel

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Adacel

CLINICAL PHARMACOLOGY

Mechanism Of Action

Tetanus

Tetanus is a disease manifested primarily by neuromuscular dysfunction caused by a potent exotoxin released 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.5,6

Diphtheria

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.7

Pertussis

Pertussis (whooping cough) is a respiratory disease caused by B pertussis. 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.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Adacel vaccine has not been evaluated for carcinogenic or mutagenic potential, or impairment of fertility.

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 Sanofi Pasteur Inc., Swiftwater, PA. The primary measures for immune response to the diphtheria and tetanus toxoids were the percentage of participants attaining an antibody level of at least 0.1 IU/mL.

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 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 laboratoryconfirmed 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%).8

In addition, the ability of Adacel vaccine to elicit a booster response (defined as rise in antibody concentration after vaccination) to the tetanus, diphtheria and pertussis antigens following vaccination was evaluated. The demonstration of a booster response depended on the antibody concentration to each antigen as established based on the 95th percentile of the pre-vaccination antibody concentrations observed in historical clinical trials with Adacel vaccine.

Immunological Evaluation In Adolescents And Adults, 10 Through 64 Years Of Age

Study Td506 was a comparative, multi-center, randomized, observer-blind, controlled trial which enrolled 4,480 participants; 2,053 adolescents (11 through 17 years of age) and 2,427 adults (18 through 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 vaccine or Td vaccine. A total of 4,461 randomized participants were vaccinated. The per-protocol immunogenicity subset included 1,270 Adacel 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 ADVERSE REACTIONS(6).]

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 and Td vaccines. (See Table 3 and Table 4.) Adacel vaccine induced pertussis antibody levels that were non-inferior to those of Swedish infants who received three doses of DAPTACEL vaccine. (See Table 5.) Acceptable booster responses to each of the pertussis antigens were also demonstrated, ie, the percentage of participants with a booster response exceeded the pre-defined lower limit. (See Table 6.)

Table 3: Pre-vaccination and Post-vaccination Antibody Responses and Booster Response Rates to Tetanus Toxoid Following Adacel Vaccine as Compared to Td Vaccine in Adolescents and Adults 11 Through 64 Years of Age

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 vaccine were non-inferior to Td vaccine (upper limit of the 95% CI on the difference for Td vaccine minus Adacel 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 4:Pre-vaccination and Post-vaccination Antibody Responses and Booster Response Rates to Diphtheria Toxoid Following Adacel Vaccine as Compared to Td Vaccine in Adolescents and Adults 11 Through 64 Years of Age

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)
% Booster1†(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 vaccine were non-inferior to Td vaccine (upper limit of the 95% CI on the difference for Td vaccine minus Adacel 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 5: Ratio of Pertussis Antibody Geometric Mean Concentrations (GMCs) Observed One Month After a Dose of Adacel Vaccine in Adolescents and Adults 11 Through 64 Years of Age 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 11-17 Years of Age Adults 18-64 Years of Age
Adacel*/DAPTACEL† GMC Ratio (95% CIs) Adacel‡/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 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 vaccine.
§ GMC following Adacel vaccine was non-inferior to GMC following DAPTACEL vaccine (lower limit of 95% CI on the ratio of GMC for Adacel vaccine divided by DAPTACEL vaccine > 0.67).

Table 6: Booster Response Rates to the Pertussis Antigens Observed One Month After a Dose of Adacel Vaccine in Adolescents and Adults 11 Through 64 Years of Age

  Adolescents 11-17 Years of Age Adults 18-64 Years of Age 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.

Study Td519 assessed the comparative immunogenicity of Adacel administered to adolescents (10 to < 11 years of age and 11 to < 12 years of age) [see ADVERSE REACTIONS] In this study non-inferiority was demonstrated for booster responses to tetanus and diphtheria toxoids, GMCs to the pertussis antigens (PT, FHA, PRN and FIM) and booster responses to the pertussis antigens PT, FHA and PRN. For FIM, non-inferiority was not demonstrated as the lower bound of the 95% CI of the difference in booster response rates (-5.96%) did not meet the predefined criterion ( > - 5% when the booster response in the older age group was > 95%).

Concomitant Hepatitis B Vaccine Administration

The concomitant use of Adacel vaccine and hepatitis B (Hep B) vaccine (Recombivax HB® , 10 mcg 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 through 14 years of age inclusive. One group received Adacel and Hep B vaccines concurrently (N = 206). The other group (N = 204) received Adacel 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 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. [See ADVERSE REACTIONS.]

Concomitant Influenza Vaccine Administration

The concomitant use of Adacel 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 and TIV vaccines concurrently (N = 359). The other group received TIV at the first visit, then 4-6 weeks later received Adacel vaccine (N = 361). Sera were obtained prior to and 4-6 weeks after Adacel vaccine, as well as 4-6 weeks after the TIV. The immune responses were comparable for concurrent and separate administration of Adacel 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. [See ADVERSE REACTIONS ]

REFERENCES

5 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.

6 Wassilak SGF, et al. Tetanus toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: WB Saunders Company; 2008. p. 805-39.

7 Vitek CR and Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: W.B. Saunders Company; 2008. p. 139-56.

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.

Last reviewed on RxList: 10/6/2014
This monograph has been modified to include the generic and brand name in many instances.

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