Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmaco-therapeutic group: Vaccines,Viral vaccine, ATC code J07BD54

Efficacy

The efficacy of GlaxoSmithKline (GSK)’s monovalent Oka varicella (Varilrix) and Priorix Tetra vaccines in preventing varicella disease has been evaluated in a large randomised multicountry clinical trial, which included GSK combined measles-mumps-rubella vaccine (Priorix) as active control. The trial has been conducted in Europe where no routine varicella vaccination was implemented at that time. Children aged 12-22 months received two doses of Priorix Tetra six weeks apart or one dose of Varilrix. Vaccine efficacy against epidemiologically confirmed or PCR (Polymerase Chain Reaction) confirmed varicella of any severity (defined using a prespecified scale) Priorix Tetra and against moderate or severe confirmed varicella was demonstrated after a primary follow-up period of 2 years (median duration 3.2 years) . Persistent efficacy was observed in the same study during the long term follow-up periods of 6 years (median duration 6.4 years) and 10 years (median duration 9.8 years). The data are presented in the Table below.

Group                  Timing             Efficacy against        Efficacy against moderate confirmed varicella of any      or severe confirmed severity                     varicella
Priorix Tetra               Year 2                 94.9%                        99.5% (2 doses)                                (97.5% CI: 92.4;96.6)        (97.5% CI: 97.5;99.9) N = 2,489                Year 6(1)              95.0%                        99.0% (95% CI: 93.6;96.2)          (95% CI: 97.7;99.6)
Year 10(1)               95.4%                        99.1%
(95% CI: 94.0;96.4)          (95% CI: 97.9;99.6)
Varilrix                 Year 2                65.4 %                        90.7% (1 dose)                                 (97.5% CI: 57.2;72.1)        (97.5% CI: 85.9;93.9) N = 2,487                Year 6(1)              67.0%                        90.3% (95% CI: 61.8;71.4)          (95% CI: 86.9;92.8)
Year 10(1)              67.2%                        89.5%
(95% CI: 62.3;71.5)          (95% CI: 86.1;92.1)
N = number of subjects enrolled and vaccinated
(1) descriptive analysis


Effectiveness
Effectiveness data suggest a higher level of protection and a decrease in breakthrough varicella following two doses of varicella-containing vaccine than following one dose.
The effectiveness of two doses of Priorix Tetra during varicella outbreaks in day care centres in Germany, where routine varicella vaccination is recommended for children as of 11 months of age, was 91% (95% CI: 65;98) against any disease and 94% (95% CI: 54;99) against moderate disease.

The effectiveness of one dose of Varilrix was estimated in different settings (outbreaks, case-control and database studies) and ranged from 20%-92% against any varicella disease and from 86%-100% against moderate or severe disease.

Immune response

Several clinical studies evaluated the immune response elicited by Priorix-Tetra administered subcutaneously. Anti-measles, anti-mumps and anti-rubella antibody titres were determined using commercially available enzyme-linked immunosorbent assays (ELISA). In addition, anti-mumps antibodies were titrated using a plaque-reduction neutralisation assay. These serological parameters are widely accepted as surrogate markers for immune protection. A modified commercial indirect immunofluorescence assay (IFA, meanwhile discontinued) and a commercial ELISA were used to compare the immune response against varicella elicited by Priorix Tetra to that observed with GSK varicella vaccine.

In three clinical trials conducted in Europe (Austria, Finland, Germany, Greece, Poland) approximately 2,000 previously unvaccinated children from 11 to 23 months of age received 2 doses of Priorix Tetra with an interval between doses of 6 weeks. Seroconversion rates and geometric mean antibody concentrations/titres (GMC/GMT) are summarized in the table below.

Antibody                          Post dose 1                                Post dose 2 Test (cut-off)
Seroconversion         GMC/GMT             Seroconversion        GMC/GMT rates              (95 % CI)               rates             (95 % CI) (95 % CI)                                  (95 % CI)
Measles
ELISA                      96.4%               3184.5                99.1%                4828.6 (150mIU/ml)            (CI: 95.5;97.2)           (CI:            (CI: 98.6;99.5)    (CI: 4644.3;5020.1) 3046.5;3328.7)
Mumps
ELISA                      91.3%                976.7                98.8%                1564.4 (231U/ml)              (CI: 90.0;92.5)    (CI: 934.8;1020.5)     (CI: 98.2;99.2)    (CI: 1514.6;1615.8) 
Neutralisation             95.4%                 147.0               99.4%                 478.4 (1:28)                 (CI: 94.3;96.3)     (CI: 138.6;155.8)     (CI: 98.9;99.7)     (CI: 455.1;503.0) Rubella
ELISA (4IU/ml)             99.7%                 62.2                99.9%                 119.7 (CI: 99.4;99.9)      (CI: 60.0;64.5)      (CI: 99.6;100)      (CI: 116.4;123.1) Varicella
IFA (1:4)                  97.2%                  97.5               99.8%                2587.8 (CI: 96.3;97.9)      (CI: 92.2;103.1)     (CI: 99.5;100)     (CI: 2454.0;2728.9) 
ELISA                      89.4%                  112.0              99.2%                2403.9 (50mIU/ml)             (CI: 87.8;90.8)      (CI: 93.5;134.0)     (CI: 98.5;99.6)    (CI: 1962.4;2944.6) 

Seroconversion rates and geometric mean antibody concentrations/titres were similar to those observed after separate vaccination with Varilrix and Priorix.

In infants vaccinated at 11 months of age, the proportion of infants with protective measles titers (i.e., > 150 mIU/mL) after the first dose is 91-92%, lower than the proportion observed when the first dose is administered since the age of 12 months.

The second dose of Priorix Tetra induced an increase in seroconversion rates and/or antibody levels for the measles, mumps and rubella vaccine components. Therefore, to avoid infection during the interval between doses it is preferred that the second dose be administered within three months following the first dose.

Data suggest a higher efficacy and a decrease in breakthrough varicella following two doses of vaccine with respect to one dose. This correlates with an increase in anti-varicella antibodies elicited by the second dose, which suggests that the second dose of varicella antigen acts as a booster.

The immune response of Priorix Tetra administered as a second dose of MMR vaccine in children 24months to 6 years of age was evaluated in 2 clinical studies. Children were previously primed with respectively an MMR vaccine or with an MMR vaccine co-administered with a live attenuated varicella vaccine. Seropositivity rates for anti-varicella antibodies were 98.1% (IFA) in children previously vaccinated with MMR and 100% in children previously vaccinated with an MMR vaccine co-administered with a live attenuated varicella vaccine. Seropositivity rates were 100% for anti- measles, mumps, rubella antibodies in both studies.

Immune response in subjects > 6 years of age

No clinical studies to evaluate the immunogenicity of Priorix-Tetra in subjects > 6 years of age have been conducted. The immunogenicity of Priorix-Tetra in subjects > 6 years is extrapolated from available data with Priorix and Varilrix.


Immune response in children aged 9 to 10 months
A clinical trial conducted in Asia (Singapore) enrolled 300 healthy children 9 to 10 months of age at the time of first vaccine dose. Of these, 153 subjects received 2 doses of Priorix Tetra with an interval between doses of 3 months and 147 subjects received Priorix and Varilrix. Seroconversion rates and geometric mean antibody concentrations/titres were similar to those observed after separate vaccination with Varilrix and Priorix. Seroconversion rates after a first dose of Priorix Tetra were comparable for all antigens except measles to those seen in 12-24 months old children in other clinical studies. The seroconversion rate reported for measles in infants 9 to 10 months of age following 1 dose of Priorix Tetra was 93.3% (95% CI: 87.6;96.9). Infants in their first year of life may not respond sufficiently to the components of the vaccine due to the possible interference with maternal antibodies. Therefore a second dose of Priorix Tetra should be given three months after the first dose.

Persistence of measles, mumps and rubella immune response

In a clinical trial in which children aged 12-22 months received two doses of Priorix-Tetra (N = 2,489), the seropositivity rates for anti-measles, mumps and rubella antibodies, in terms of subjects with an antibody concentration equal to or above defined threshold, observed after follow-up periods of 2 , 6 and 10 years are presented in the Table below:

Timing                                                  Antibody
Test (cut-off)
Measles                          Mumps                  Rubella
ELISA (150 mIU/ml)              ELISA (231 U/ml)          ELISA (4 IU/ml) Year 2                         99.1%                          90.5%                   100% Year 6                         99.0%                          90.5%                   99.8% Year 10                        98.5%                          90.0%                   97.7% ELISA: Enzyme Linked Immuno Sorbent Assay

As robust efficacy data against varicella disease up to 10 years are provided above (see subsection “Efficacy”) and since there is no threshold for protection against varicella disease established with the obtained immunological data, anti-varicella antibody persistence data are not provided.


Post-Marketing Observational Safety Surveillance Study
The risk of febrile convulsions following the first dose of Priorix Tetra was assessed in a retrospective database analysis in children aged 9 to 30 months (see section 4.8).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Not applicable.