Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Pertussis, purified antigen, combination with toxoids.
ATC code: J07AJ52

Clinical trials
The immune responses observed one month after vaccination with ADACEL in 265 children, 527 adolescents and 743 adults are shown in the table below.

Table 2: Immune response of children, adolescents and adults one month after vaccination with ADACEL

Antibody                           Criteria                 Children              Adolescents               Adults (4 - 6 years)1        (11 - 17 years)2        (18 - 64 years)2
(N=265)                (N=527)                 (N=743)
%                      %                       %
Diphtheria (SN, IU/mL)                ≥0.1                              100                     99.8                    94.1 Tetanus (ELISA, IU/mL or              ≥0.1                              100                   100                      100 EU/mL)
Pertussis (ELISA, EU/mL)              Booster Response3
PT                                                                        91.9                  92.0                     84.4 FHA                                                                       88.1                  85.6                     82.7 PRN                                                                       94.6                  94.5                     93.8 FIM                                                                       94.3                  94.9                     85.9 

DTaP: diphtheria toxoid [paediatric dose], tetanus and acellular pertussis; ELISA: Enzyme Linked Immunoassay; EU: ELISA units; IU: international units; N: number of participants with available data; SN: seroneutralisation.
1
Study Td508 was conducted in Canada with children 4-6 years of age.
2
Study Td506 was conducted in the United States with adolescents 11-17 years of age and adults 18-64 years of age.
3
For children in Study Td508 who were previously primed with DTaP at 2, 4, 6 and 18 months of age, a booster response is defined as a 4-fold increase in concentration of anti-pertussis antibodies. For adolescents and adults in Study Td506, a booster response is defined as a 2-fold increase in concentration of anti-pertussis antibodies in participants with high pre-vaccination concentration and a 4-fold increase in participants with low pre-vaccination concentration.

The safety and immunogenicity of ADACEL in adults and adolescents was shown to be comparable to that observed with a single dose of an adult formulation diphtheria-tetanus (Td) adsorbed vaccine containing the same amount of tetanus and diphtheria toxoids.

Serological correlates for protection against pertussis have not been established. On comparison with data from the Sweden I pertussis efficacy trials conducted between 1992 and 1996, where primary immunization with Sanofi Pasteur acellular pertussis infant DTaP formulation confirmed a protective efficacy of 85% against pertussis disease, it is considered that ADACEL had elicited protective immune responses. The pertussis antibody levels for all antigens following a booster dose of ADACEL in adolescents and adults exceeded those observed in a household contact study nested within the efficacy trial.


Table 3: Ratio of pertussis antibody GMCs observed one month after a dose of ADACEL in adolescents and adults compared with those observed in infants one month following vaccination at 2, 4 and 6 months of age in the Sweden I efficacy trial with DTaP (PPI Population1)

Adolescents                                  Adults

(11-17 years)2                           (18-64 years)2
ADACEL/DTaP3                             ADACEL/DTaP3
GMC Ratio                                GMC Ratio
(95% CIs)4                               (95% CIs)4

Participants                     N=524-526                                   N=741 
3.6                                       2.1
Anti-PT
(2.8, 4.5)                                (1.6, 2.7)
5.4                                       4.8
Anti-FHA
(4.5, 6.5)                                (3.9, 5.9)
3.2                                       3.2
Anti-PRN
(2.5, 4.1)                                (2.3, 4.4)
5.3                                      2.5
Anti-FIM
(3.9, 7.1)                                (1.8, 3.5)

DTaP: diphtheria toxoid [paediatric dose], tetanus and acellular pertussis; GMC: Geometric Mean Concentration; N: number of participants with available data; PPI: per protocol immunogenicity
1
Eligible participants for whom immunogenicity data were available.
2
Study Td506 was conducted in the United States with adolescents 11-17 years of age and adults 18-64 years of age. Antibody GMCs, measured in ELISA units were calculated separately for infants, adolescents and adults.
3
N = 80, number of infants who received DTaP at 2, 4 and 6 months of age with available data post-dose 3 (sera from the Sweden I Efficacy Trial tested contemporaneously with samples from study Td506).
4
GMCs following ADACELwere non-inferior to GMCs following DTaP (lower limit of 95% CI on the ratio of GMCs for ADACEL divided by DTaP >0.67).


Antibody persistence
Serology follow-up studies were conducted at 3, 5 and 10 years, in individuals previously immunized with a single booster dose of ADACEL. Persistence of seroprotection to diphtheria and tetanus, and seropositivity to pertussis is summarized in Table 4.

Table 4: Persistence of Seroprotection/Seropositivity Rates (%) in Children, Adolescents and Adults at 3-, 5- and 10- years following a dose of ADACEL (PPI Population1)

Children                Adolescents                              Adults (4-6                 (11-17 years)3                         (18-64 years)3 years)2
Time since ADACEL dose            5 years     3 years     5 years        10 years    3 years      5 years       10 years Participants                      N=128-      N=300       N=204-         N=28-39      N=292       N=237-        N=120- 150                     206                                     238           136 
Antibody                                                    % Seroprotection/Seropositivity 
≥ 0.1           86.0        97.0         95.1          94.9         81.2         81.1         84.6 Diphtheria
(SN, IU/mL)
≥ 0.01           100         100         100            100         95.2         93.7         99.3 Tetanus
≥ 0.1           97.3         100         100            100         99.0         97.1          100 (ELISA, IU/mL)
Pertussis
(ELISA,
EU/mL)
PT              Sero-           63.3        97.3         85.4          82.1         94.2         89.1         85.8 positivity4
FHA                             97.3        100          99.5          100          99.3         100          100 PRN                             95.3        99.7         98.5          100          98.6         97.1         99.3 FIM                             98.7        98.3         99.5          100          93.5         99.6         98.5 ELISA: Enzyme Linked Immunoassay; EU: ELISA units; IU: international units; N: number of participants with available data; PPI: per protocol immunogenicity; SN: seroneutralisation; 1
Eligible participants for whom immunogenicity data were available for at least one antibody at the specified time-point.
2
Study Td508 was conducted in Canada with children 4-6 years of age.
3
Study Td506 was conducted in the United States with adolescents 11-17 years of age and adults 18-64 years of age.
4
Percentage of participants with antibodies ≥ 5 EU/mL for PT, ≥ 3 EU/mL for FHA and PRN, and ≥ 17 EU/mL for FIM for the 3 year follow-up; ≥ 4 EU/mL for PT, PRN and FIM, and ≥ 3 EU/mL for FHA for the 5-year and 10-year follow-up.

Immunogenicity in persons not previously vaccinated or with an unknown vaccination status 
After administration of one dose of REPEVAX (Tdap-IPV; containing the same amounts of tetanus, diphtheria and pertussis antigens as ADACEL) to 330 adults ≥40 years of age that had not received any diphtheria- and tetanus-containing vaccine in the past 20 years:
• ≥95.8% of adults were seropositive (≥ 5 EU/mL) for antibodies to all vaccine-containing pertussis antigens,
• 82.4% and 92.7% were seroprotected against diphtheria at a threshold ≥0.1 and ≥0.01 IU/mL, respectively,
• 98.5% and 99.7% were seroprotected against tetanus at a threshold ≥0.1 and ≥0.01 IU/mL, respectively,
• and ≥98.8% were seroprotected against polio (types 1, 2 and 3) at a threshold ≥1:8 dilution.

After administration of two additional doses of diphtheria- tetanus- and polio-containing vaccine to 316 subjects, one and six months after the first dose, the seroprotection rates against diphtheria were 94.6% and 100% (≥0.1 and ≥ 0.01 IU/mL, respectively), against tetanus 100% (≥0.1 IU/mL), and against polio (types 1, 2 and 3) 100% (≥1:8 dilution).

Immunogenicity following repeat vaccination

The immunogenicity of ADACEL following repeat vaccination 10 years after a previous dose of ADACEL or REPEVAX, has been evaluated. One month post-vaccination ≥ 98.5% of study participants achieved seroprotective antibody levels (≥ 0.1 IU/ml) for diphtheria and tetanus, and ≥ 84% achieved booster responses to the pertussis antigens. (A pertussis booster response was defined as a post-vaccination antibody concentration ≥ 4 times the LLOQ if the pre-vaccination level was < LLOQ; ≥ 4 times the pre- vaccination level if that was ≥ LLOQ but < 4 times LLOQ; or ≥ 2 times the pre-vaccination level if that was ≥ 4 times the LLOQ).

Based on the serology follow-up and repeat vaccination data, ADACEL can be used instead of a dT vaccine to boost immunity to pertussis in addition to diphtheria and tetanus.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Evaluation of pharmacokinetic properties is not required for vaccines.