Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: Bacterial and viral vaccines combined, ATC code: J07CA09 
Immunogenicity

The immunogenicity of Infanrix hexa has been evaluated in clinical studies from 6 weeks of age. The vaccine was assessed in 2-dose 3-dose priming schedules, including the schedule for the Expanded Program on Immunisation, and as a booster dose. The results of these clinical studies are summarised in the tables below.

After a 3-dose primary vaccination schedule, at least 95.7% of infants had developed seroprotective or seropositive antibody levels against each of the vaccine antigens. After booster vaccination (post-dose 4), at least 98.4% of children had developed seroprotective or seropositive antibody levels against each of the vaccine antigens.

Percentage of subjects with antibody titres indicative of seroprotection / seropositivity one month after 3-dose primary and booster vaccination with Infanrix hexa 
Antibody             Post-dose 3                                         Post-dose 4 (cut-off)                                                                (Booster vaccination during the second year of life following a 3-dose primary course)

2-3-4        2-4-6          3-4-5          6-10-14 months       months         months         weeks
N=2009
N= 196       N= 1693        N= 1055        N= 265
(12 studies)
(2           (6 studies)    (6 studies)    (1 study) studies)
%            %              %              %           %
Anti-diphtheria     100.0        99.8           99.7           99.2        99.9 (0.1 IU/ml) †
Anti-tetanus        100.0        100.0          100.0          99.6        99.9 (0.1 IU/ml) †
Anti-PT             100.0        100.0          99.8           99.6        99.9 (5 EL.U/ml)
Anti-FHA            100.0        100.0          100.0          100.0       99.9 (5 EL.U/ml)
Anti-PRN            100.0        100.0          99.7           98.9        99.5 (5 EL.U/ml)
Anti-HBs            99.5         98.9           98.0           98.5*       98.4 (10 mIU/ml) †
Anti-Polio type     100.0        99.9           99.7           99.6        99.9 1
(1/8 dilution) †
Anti-Polio type     97.8         99.3           98.9           95.7        99.9 2
(1/8 dilution) †
Anti-Polio type     100.0        99.7           99.7           99.6        99.9 3
(1/8 dilution) †
Anti-PRP            96.4         96.6           96.8           97.4        99.7** (0.15 g/ml) †

N = number of subjects
* in a subgroup of infants not administered hepatitis B vaccine at birth, 77.7% of subjects had anti-HBs titres ≥ 10 mIU/ml
** Post booster, 98.4% of subjects had anti-PRP concentration ≥ 1 μg/ml indicative of long- term protection
† cut-off accepted as indicative of protection

Serological correlates of protection have been established for diphtheria, tetanus, polio, Hepatitis B and Hib. For pertussis there is no serological correlate of protection. However, as the immune response to pertussis antigens following Infanrix hexa administration is equivalent to that of Infanrix, the protective efficacy of the two vaccines is expected to be equivalent.


Efficacy in protecting against pertussis
The clinical protection of the pertussis component of Infanrix (DTPa), against WHO-defined typical pertussis ( 21 days of paroxysmal cough) was demonstrated after 3-dose primary immunisation in the studies tabulated below:

Vaccine
Study                 Country     Schedule                     Considerations efficacy

Household contact    Germany      3,4,5 months    88.7%      Based on data collected from secondary study (prospective                                           contacts in households where there was an blinded)                                                     index case with typical pertussis Efficacy study       Italy        2,4,6 months    84%        In a follow-up of the same cohort, the (NIH sponsored)                                              efficacy was confirmed up to 60 months after completion of primary vaccination without administration of a booster dose of pertussis.

Persistence of the immune response

The persistence of the immune response to a 3-dose primary (at 2-3-4, 3-4-5 or 2-4-6 months of age) and booster (in the second year of life) schedule with Infanrix hexa was evaluated in children 4-8 years of age. Protective immunity against the three poliovirus types and PRP was observed in at least 91.0% of children and against diphtheria and tetanus in at least 64.7% of children. At least 25.4% (anti-PT), 97.5% (anti-FHA) and 87.0% (anti-PRN) of children were seropositive against the pertussis components.
Percentage of subjects with antibody titres indicative of seroprotection / seropositivity after primary and booster vaccination with Infanrix hexa

Antibody             Children at 4-5 years of age         Children at 7-8 years of age (cut-off)            N             %                      N              % Anti-diphtheria
198           68.7*                  51             66.7
(0.1 IU/ml)
Anti-tetanus
198           74.7                   51             64.7
(0.1 IU/ml)
Anti-PT
197           25.4                   161            32.3
(5 EL.U/ml)
Anti-FHA
197           97.5                   161            98.1
(5 EL.U/ml)
Anti-PRN
198           90.9                   162            87.0
(5 EL.U/ml)
Anti-HBs             250§          85.3                   207§           72.1 (10 mIU/ml)          171§          86.4                   149§           77.2 Anti-Polio type 1
185           95.7                   145            91.0
(1/8 dilution)
Anti-Polio type 2
187           95.7                   148            91.2
(1/8 dilution)
Anti-Polio type 3
174           97.7                   144            97.2
(1/8 dilution)
Anti-PRP
198           98.0                   193            99.5
(0.15 g/ml)
N = number of subjects
* Samples tested by ELISA to have anti-diphtheria antibody concentrations < 0.1 IU/ml were re-tested using Vero-cell neutralisation assay (seroprotection cut-off ≥ 0.016 IU/ml): 96.5% of the subjects were seroprotected
§ Number of subjects from 2 clinical studies

With regards to hepatitis B, seroprotective antibody concentrations (≥10 mIU/ml) following a 3-dose primary and booster schedule with Infanrix hexa have been shown to persist in ≥ 85% of subjects 4-5 years of age , in ≥72% of subjects 7-8 years of age , in ≥60% of subjects 12-13 years of age and in 53.7% of subjects 14-15 years of age.

Hepatitis B immunological memory was confirmed in children 4 to 15 years of age. These children had received Infanrix hexa as primary and booster vaccination in infancy, and when an additional dose of monovalent HBV vaccine was administered, protective immunity was observed in at least 93% of subjects.

Immunogenicity in preterm infants
The immunogenicity of Infanrix hexa was evaluated across three studies including approximately 300 preterm infants (born after a gestation period of 24 to 36 weeks) following a 3-dose primary vaccination course at 2, 4 and 6 months of age. The immunogenicity of a booster dose at 18 to 24 months of age was evaluated in approximately 200 preterm infants.

One month after primary vaccination at least 98.7% of subjects were seroprotected against diphtheria, tetanus and poliovirus types 1 and 2; at least 90.9% had seroprotective antibody levels against the hepatitis B, PRP and poliovirus type 3 antigens; and all subjects were seropositive for antibodies against FHA and PRN while 94.9% were seropositive for anti-PT antibodies.

One month after the booster dose at least 98.4% of subjects had seroprotective or seropositive antibody levels against each of the antigens except against PT (at least 96.8%) and hepatitis B (at least 88.7%). The response to the booster dose in terms of fold increases in antibody concentrations (15- to 235-fold), indicate that preterm infants were adequately primed for all the antigens of Infanrix hexa.

In a follow-up study conducted in 74 children, approximately 2.5 to 3 years after the booster dose, 85.3% of the children were still seroprotected against hepatitis B and at least 95.7% were seroprotected against the three poliovirus types and PRP.

Post marketing experience

The effectiveness of the Hib component of Infanrix hexa was investigated via an extensive post-marketing surveillance study conducted in Germany. Over a seven year follow-up period, the effectiveness of the Hib components of two hexavalent vaccines, of which one was Infanrix hexa, was 89.6% for a full primary series and 100% for a full primary series plus booster dose (irrespective of the Hib vaccine used for priming).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Evaluation of pharmacokinetic properties is not required for vaccines.