Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Hepatitis B vaccine, ATC code: J07BC01

Mechanism of action

Engerix B induces specific humoral antibodies against HBsAg (anti-HBs antibodies). Anti-HBs antibody concentrations > m10 IU/ml correlate with protection to HBV infection.

Pharmacodynamic effects
Subjects with increased risk of HBV exposure In field studies, a protective efficacy between 95% and 100% was demonstrated in neonates, children and adults at risk.

In healthy subjects in high risk area, one month after the last vaccine dose, a 95% protective efficacy (serum anti HBs IgG ≥ 10 mIU/ml) was demonstrated in neonates of HBeAg positive mothers, immunised according to the 0, 1, 2 and 12 month or 0, 1 and 6 month schedules without concomitant administration of hepatitis B immunoglobulin (HBIg) at birth. However, simultaneous administration of HBIg and vaccine at birth increased the protective efficacy to 98%.

Neonates born to mothers who were hepatitis B virus carriers (HBsAg positive with or without HBeAg) and who did not receive HBIg at birth received a challenge dose of Engerix B twenty years after primary vaccination (3-dose or 4-dose schedules).
The seroprotection rate before and after the challenge dose has been evaluated: 
Seroprotection rate                                   N     n      %          95% CI LL      UL
Pre-challenge                                        72    39     54.2     42.0    66.0 Post-challenge                                       75    74     98.7     92.8    100 N = number of subjects with available results n = number of subjects with concentration equal to or above 10mIU/ml % = percentage of subjects with concentration equal to or above 10mIU/ml 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = at the time of administration of the challenge dose / POST = one month after challenge dose


The anamnestic response according to the pre-challenge serostatus was also evaluated: 

Anamnestic response
95% CI
Pre-challenge status                              N         n        %      LL      UL Subjects < 10 mIU/ml                             33         31      93.9   79.8     99.3 Subjects ≥ 10 mIU/ml                             39         39      100    91.0     100 Total                                            72         70     97.2    90.3     99.7 Stratification based on last available time point prior to challenge dose: - subjects <10 mIU/ml = subjects with antibody concentration <10 mIU/ml prior to the challenge dose
- subjects ≥10 mIU/ml = subjects with antibody concentration ≥10 mIU/ml prior to the challenge dose
Anamnestic response is defined as:
- anti-HBs antibody concentrations ≥ 10 mIU/ml in subjects who were seronegative before the challenge dose, or
- an increase in anti-HBs antibody concentrations by at least 4-fold in subjects who were seropositive before the challenge dose.
N = number of subjects with both pre- and post-vaccination results available n = number of responders
% = percentage of responders
95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit General paediatric population:

- Seroprotection rates in healthy subjects up to and including 15 years of age: The table below summarizes seroprotection rates (i.e. percentages of subjects with anti-HBs antibody concentrations  10 IU/l) obtained in clinical studies with the different schedules mentioned in section 4.2:



Population                         Schedule                  Seroprotection rate 
Healthy subjects up to and         0, 1, 6 months                 at month 7:  96 % including 15 years of age
0, 1, 2 – 12 months            at month 1: 15 % at month 3: 89 % at month 13: 95.8 %

The data in the above table were generated with thiomersal containing vaccines.
Two additional clinical studies conducted with the current formulation of Engerix B, which does not contain thiomersal, among healthy infants and adults, elicit similar seroprotection rates as compared to former thiomersal containing formulations of Engerix B.

-   Persistence of immune response in healthy subjects from 11 years up to and including 15 years of age:
The long-term immune response was assessed in a clinical trial in subjects from 11 years up to and including 15 years of age at the time of primary vaccination.
Seroprotection rates (i.e. percentages of subjects with anti-HBs antibody concentrations ≥ 10 IU/l) with the two different dosages and schedules were evaluated up to 66 months after the first dose of the primary vaccination and are presented in the table below (ATP cohort for efficacy):

Months after the first vaccine dose:
Vaccination schedule         2         6         7          30         42        54         66 Seroprotection rate
Engerix B 10µg           55.8%       87.6%   98.2%*       96.9%      92.5%     94.7%       91.4% (0, 1, 6 months)
Engerix B 20µg           11.3%       26.4%      96.7%*   87.1%      83.7%      84.4%       79.5% (0, 6 months)
* At month 7, 97.3% and 88.8% of subjects aged 11 to 15 years vaccinated with Engerix B 10 µg/0.5 ml (0, 1, 6 months schedule) or Engerix B 20 µg/1 ml (0, 6 months schedule) respectively developed anti-HBs antibody concentrations > 100mIU/ml. Geometric Mean Concentrations (GMC) were 7238 mIU/ml and 2739 mIU/ml respectively.

All subjects in both vaccine groups (N=74) received a challenge dose 72 to 78 months after primary vaccination. One month later, all subjects mounted an anamnestic response with a GMC increase of 108 and 95 fold from the pre to the post challenge time points in the 2-dose and 3-dose priming schedule respectively and were shown to be seroprotected. These data suggest that immune memory was induced in all subjects who responded to primary vaccination, even among those who had lost seroprotection at Month 66.


- Healthy subjects 16 years of age and above:
The table below summarizes seroprotection rates (i.e. percentages of subjects with anti-HBs antibody concentrations  10 IU/l) obtained in clinical studies with Engerix B 20µg, given according to the different schedules mentioned in Section 4.2: 


Population                          Schedule                     Seroprotection rate 
Healthy subjects 16 years of     0, 1, 6 months                     at month 7:  96 % age and above
0, 1, 2 – 12 months                at month 1: 15 % at month 3: 89 % at month 13: 95.8 %

Healthy subjects 18 years of     0, 7, 21 days – 12 months          at day 28: 65.2 % age and above                                                       at month 2: 76 % at month 13: 98.6 %


The data in the above table were generated with thiomersal containing vaccines. Two additional clinical studies conducted with the current formulation of Engerix B, which contains no thiomersal, among healthy infants and adults, elicit similar seroprotection rates as compared to former thiomersal containing formulations of Engerix B.



-     Persistence of immune response and rechallenge of subjects aged 15 to 16 years, 14 years after primary vaccination:


Seroprotection rates before and after a challenge dose have been evaluated in subjects aged 15 to 16 years who were vaccinated with 3 doses of ENGERIX B during the first two years of life:
Seroprotection rate                                         N      n    %         95% CI LL      UL
Pre-challenge                                               292   191   65.4   59.6    70.9 Post-challenge                                              292   286   97.9   95.6    99.2 N = number of subjects with available results n = number of subjects with concentration equal to or above 10mIU/ml % = percentage of subjects with concentration equal to or above 10mIU/ml 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PRE = prior to the challenge dose / POST= one month after challenge dose 
Anamnestic response has been evaluated according to pre-challenge serostatus in subjects aged 15 to 16 years who were vaccinated with 3 doses of ENGERIX B during the first two years of life:
Anamnestic response
95% CI
Pre-challenge status                                  N           n     %         LL      UL Subjects < 10 mIU/ml                                 101          95   94.1      87.5     97.8 Subjects ≥ 10 mIU/ml                                 190         187   98.4      95.5     99.7 Total                                                291         282   96.9      94.2     98.6 Stratification based on last available time point prior to booster dose: - subjects <10 mIU/ml = subjects with antibody concentration <10 mIU/ml prior to the challenge dose
- subjects ≥10 mIU/ml = subjects with antibody concentration ≥10 mIU/ml prior to the challenge dose
Anamnestic response is defined as:
- anti-HBs antibody concentrations ≥ 10 mIU/ml in subjects who were seronegative before the challenge dose, or
- an increase in anti-HBs antibody concentrations by at least 4-fold in subjects who were seropositive before the challenge dose.
N = number of subjects with both pre- and post-vaccination results available n = number of responders
% = percentage of responders
95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit 

The primary endpoint of the study, defined as the percentage of subjects with anti-HBs antibody concentrations ≥ 100 mIU/mL one month after the challenge dose, was calculated at 90.8% (95% CI: 86.8; 93.8). The anti-HBs antibody GMC increased by 156-fold (from 26.5 to 4134.9 mIU/mL) as a response to the challenge dose.


Similar data with respect to seroprotection rates and anamnestic response were obtained in subjects (N=279) aged 12 - 13 years.

• Patients with renal insufficiency including patients undergoing haemodialysis: The seroprotection rates in subjects 16 years of age and above with renal insufficiency including patient undergoing haemodialysis were evaluated 3 and 7 months after the first dose of the primary vaccination and are presented in the Table below:


Age (years)                         Schedule                      Seroprotection rate 16 and above                       0, 1, 2, 6 months                   at month 3: 55.4 % (2 x 20 µg)                         at month 7: 87.1 %


• Patients with type II diabetes:
The seroprotection rates in subjects 20 years of age and above with type II diabetes were evaluated one month after the last dose of the primary vaccination and are presented in the Table below:


Age (years)                         Schedule                      Seroprotection rate at Month 7
20-39                                                                  88.5 %
40-49                              0, 1, 6 months                      81.2 %
50-59                              (20 µg)                             83.2 %  60                                                                   58.2 % 

• Reduction in the incidence of hepatocellular carcinoma in children: A clear link has been demonstrated between hepatitis B infection and the occurrence of hepatocellular carcinoma (HCC). The prevention of hepatitis B by vaccination results in a reduction of the incidence of HCC, as has been observed in Taiwan in children aged 6-14 years.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties
Not applicable.