Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Bacterial and viral vaccines combined. Vaccine against diphtheria, tetanus, pertussis and poliomyelitis
ATC Code: J07CA02

Clinical trials
The immune responses of adults, adolescents and children 3 to 6 years of age one- month after vaccination with ADACEL POLIO are shown in the table below. The use of ADACEL POLIO in children aged 3 to 5 years is based upon studies in which ADACEL POLIO was given as the fourth dose (first booster) of diphtheria, tetanus, pertussis and poliomyelitis vaccines.
Adults and       Children 5-6 Children 3-5
Table 2: Immune responses 4
Criteria  Adolescents*       years old†     years old‡ weeks after vaccination Antigen
(n = 994)         (n = 240)      (n = 148)
Diphtheria                          ≥0.1 IU/mL            92.8%            99.4%            100% Tetanus                             ≥0.1 IU/mL§           100%             99.5%            100% Pertussis
Pertussis Toxoid                    ≥5 EU/mL**            99.7%            91.2%            99.3% Filamentous Haemagglutinin          ≥5 EU/mL**            99.9%            99.1%            99.3% Pertactin                           ≥5 EU/mL**            99.6%            100%             100% Fimbriae Types 2 and 3              ≥5 EU/mL**            99.8%            99.5%            100% Polio 1                          ≥1:8 Dilution        99.9%           100%                  100% Polio 2                          ≥1:8 Dilution         100%           100%                  100% Polio 3                          ≥1:8 Dilution         100%           100%                  100% * From the age of 10 years onwards
† Primed with DTaP at 3 and 5 months with a booster at 12 months of age ‡ Primed with DTwP at 2, 3 and 4 months of age
§ Measured by ELISA
** EU = ELISA units: Antibody levels of >5 EU/mL were postulated as possible surrogate markers for protection against pertussis by Storsaeter J. et al, Vaccine 1998;16:1907-16.
The safety and immunogenicity of ADACEL-POLIO in adults and adolescents was shown to be comparable to that observed with a single booster dose of Td adsorbed or Td Polio adsorbed vaccines containing a similar amount of tetanus and diphtheria toxoids and inactivated poliovirus types 1, 2 and 3.
The lower response to diphtheria toxoid in adults probably reflected the inclusion of some participants with an uncertain or incomplete immunization history.
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 Limited's acellular pertussis infant DTaP formulation confirmed a protective efficacy of 85% against pertussis disease, it is considered that ADACEL-POLIO had elicited protective immune responses.
In a subsequent study, robust immune responses were observed following a single dose of ADACEL-POLIO in UK children 3.5 to 4.0 years of age previously primed with either an acellular pertussis combination vaccine (DTaP-IPV-Hib) or whole cell pertussis combination vaccine (DTwP//Hib) and OPV.
Antibody persistence
Pivotal studies conducted with ADACEL provide serology follow-up data 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 summarised in Table 3.
Table 3: Persistence of Seroprotection/Seropositivity Rates in Children, Adolescents and Adults at 3-, 5- and 10- years following a dose of ADACEL (Tdap component of ADACEL-POLIO) (PPI Population1)
Children (4-         Adolescents                       Adults
6 years)2         (11-17 years)2                 (18-64 years)2
5 years       3       5 years 10 years 3 years 5 years 10 years
Time point years
Antibody                 N=128-150 N=300         N=204-   N=28-39     N=292     N=237-     N=120- 206                            238        136
Diphtheria    ≥ 0.1      86.0          97.0      95.1     94.9       81.2      81.1      84.6 (SN, IU/mL)   ≥ 0.01     100.0         100.0     100.0    100.0      95.2      93.7      99.3 Tetanus
(ELISA,       ≥ 0.1      97.3          100.0     100.0    100.0      99.0      97.1      100.0 IU/mL)
Pertussis
(ELISA,
IU/mL)
PT            Sero-       63.3         97.3      85.4     82.1       94.2      89.1      85.8 positivity3
FHA                       97.3         100.0     99.5     100.0      99.3      100.0     100.0 PRN                      95.3          99.7      98.5     100.0      98.6      97.1      99.3 FIM                       98.7       98.3     99.5      100.0       93.5       99.6    98.5 N = number of subjects with available data; SN: seroneutralisation; ELISA: Enzyme Linked Immunoassay
1
Eligible subjects for whom immunogenicity data was available for at least one antigen at the specified time-point.
2
Age at which subjects received a dose of ADACEL

3
Percentage of subjects with antibodies ≥ 4 EU/mL for PT, FHA and PRN, and ≥ 17 EU/mL for FIM for the 3 year follow-up; ≥ 4 EU/mL for PT, FIM and PRN, and ≥ 3 EU/mL for FHA for the 5-year and 10-year follow-up
In serology follow-up studies conducted with ADACEL-POLIO, seroprotective antibody levels (≥1:8 dilution) for each poliovirus (type1, 2 and 3) were maintained in 95% to 100% of the children, adolescents and adults at the 5-year follow-up time point, and in 100% of the adolescents at the 10-year follow-up time point.
Immunogenicity following repeat vaccination
The immunogenicity of ADACEL following repeat vaccination 10 years after a previous dose of ADACEL or ADACEL-POLIO, 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-POLIO can be used instead of a dT vaccine or dT-IPV vaccine to boost immunity to pertussis in addition diphtheria, tetanus and polio.
Immunogenicity in naïve subjects
After administration of one dose of ADACEL-POLIO 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 IU/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) (see Table 4).
Table 4: Serological immune status (seroprotection/seroresponse rates and GMC/GMT) before vaccination and after each dose of a 3 dose-vaccination schedule including ADACEL-POLIO (Dose 1) followed by 2 doses of REVAXIS 1 and 6 months later (Dose 2 and 3) in subjects vaccinated according to protocol (FAS)
Antigen             Criteria Pre-vaccination Post-dose 1              Post-dose 2       Post-dose 3 ADACEL-             REVAXIS          REVAXIS
POLIO
N=330              N=330             N=325            N=316
Diphtheria       GMC               0.059              0.813            1.373             1.489 (SN, IU/mL)      95%CI         [0.046; 0.077]     [0.624; 1.059]   [1.100; 1.715]    [1.262; 1.757] ≥0.1             44.5%              82.4%             90.5%             94.6% 95%CI          [39.1; 50.1]       [77.9; 86.4]     [86.7; 93.4]      [91.5; 96.8] ≥0.01            72.4%              92.7%             96.0%             100% 95%CI          [67.3; 77.2]       [89.4; 95.3]     [93.3; 97.9]      [98.8; 100] 
Antigen           Criteria   Pre-vaccination        Post-dose 1      Post-dose 2       Post-dose 3 ADACEL-          REVAXIS           REVAXIS
POLIO
Tetanus         GMC               0.48                  6.82             7.60             5.46 (ELISA, IU/mL) 95%CI           [0.39;0.60]           [5.92;7.87]      [6.77;8.52]      [5.01;5.96] ≥0.1             81.2%                 98.5%             100%             100% 95%CI          [76.6; 85.3]          [96.5; 99.5]     [98.9; 100]      [98.8; 100] ≥0.01            92.4%                 99.7%             100%             100% 95%CI          [89.0; 95.0]          [98.3; 100]      [98.9; 100]      [98.8; 100] Poliomyelitis (SN, 1/dil)
Type 1          GMT               162.6                2869.0           2320.2           1601.9 95%CI         [133.6; 198.0]       [2432.9; 3383.4] [2010.9; 2677.0]    [1425.4; 1800.3]
≥8               93.3%                 99.4%             100%             100% 95%CI          [90.1; 95.8]          [97.8; 99.9]     [98.9; 100]      [98.8; 100] Type 2          GMT               164.5                3829.7           3256.0           2107.2 95%CI         [137.6;196.8]        [3258.5;4501.1] [2818.2;3761.7] [1855.7;2392.8] ≥8               95.5%                  100%             100%             100% 95%CI          [92.6; 97.4]          [98.9; 100]      [98.9; 100]      [98.8; 100] Type 3          GMT               69.0                 5011.4           3615.6           2125.8 95%CI          [56.9; 83.6]        [4177.4; 6012.0] [3100.5; 4216.4]    [1875.5; 2409.6]
≥8               89.1%                 98.8%            99.7%             100% 95%CI          [85.2; 92.2]          [96.9; 99.7]     [98.3; 100]      [98.8; 100] Pertussis (ELISA, EU/mL)
PT              GMC                7.7                  41.3
95%CI           [6.8; 8.7]           [36.7; 46.5]
≥5                  -                  96.3%               -                - 95%CI                                [93.6; 98.1]
FHA             GMC               28.5                  186.7
95%CI          [25.5; 31.8]         [169.6; 205.6]
≥5                  -                   100%               -                - 95%CI                                [98.9; 100]
PRN             GMC                7.7                  328.6
95%CI           [6.7; 8.9]          [273.0; 395.6]
≥5                  -                  99.4%               -                - 95%CI                                [97.8; 99.9]
FIM2&3          GMC                6.1                  149.6
95%CI           [5.2; 7.1]          [123.6; 181.0]
≥5                  -                  95.8%               -                - 95%CI                                [93.0; 97.7]

GMC: Geometric mean of antibody concentrations; GMT: Geometric mean of antibody titres; CI: Confidence Interval; SN: seroneutralisation; ELISA: Enzyme Linked Immunoassay; dil: dilution
FAS: Full Analysis Set – includes all subjects who received the study vaccine dose and for whom the post-vaccination immunogenicity evaluation was available.

Pharmacokinetic Properties

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