Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Vaccines, Viral Vaccine; ATC code: J07BD54.
Efficacy
Formal studies to evaluate the efficacy of ProQuad have not been performed. However, the efficacy of Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by MSD has been demonstrated in numerous studies.

Efficacy of the measles, mumps, and rubella components of ProQuad was previously established in a series of double-blind controlled field trials with the monovalent vaccines manufactured by MSD, which demonstrated a high degree of protective efficacy. In these studies seroconversion in response to vaccination against measles, mumps, and rubella paralleled protection from these diseases. ProQuad elicits rates of antibody responses against measles, mumps, and rubella similar to those observed after vaccination with the measles, mumps, and rubella vaccine manufactured by MSD.

More than 518 million doses of the measles, mumps, and rubella vaccine manufactured by MSD have been distributed worldwide (1978 to 2007). Widespread use of a 2-dose vaccination schedule in the United States and countries such as Finland and Sweden has led to a >99% reduction in the incidence of each of the 3 targeted diseases.

In combined clinical trials of a single dose of Varicella Vaccine live (Oka/Merck) in healthy children, the protective efficacy of the vaccine against all severities of varicella disease ranged from 81% to 100%. In a large case-control study, the vaccine was estimated to be 85% effective against all forms of varicella and 97% effective against moderately severe and severe disease.

In a study comparing 1 dose (N=1114) to 2 doses (N=1102) of Varicella Vaccine live (Oka/Merck), the estimated vaccine efficacy against all severities of varicella disease for the 10-year observation period was 94% for 1 dose and 98% for 2 doses (p<0.001). Over the 10-year observation period, the cumulative rate of varicella was 7.5% after 1 dose and 2.2% after 2 doses. Most cases of varicella reported in recipients of 1 dose or 2 doses of vaccine were mild.

Antibody responses against varicella virus ≥5 gpELISA Units/mL in the glycoprotein enzyme-linked immunosorbent assay (gpELISA, a highly sensitive assay which is not commercially available) have been shown to be highly correlated with long-term protection. Clinical studies have shown that immunization with ProQuad elicits rates of antibody responses against varicella virus ≥5 gpELISA Units/mL similar to those observed after vaccination with Varicella Vaccine live (Oka/Merck).

Immunogenicity
Immunogenicity was studied in children 12 through 23 months of age with a negative clinical history of measles, mumps, rubella, and varicella who participated in 5 randomised clinical trials. The immunogenicity of the current refrigerator-stable formulation was shown to be similar to the immunogenicity of the earlier formulation of ProQuad six weeks after a single dose of the vaccine. The immunogenicity of a single dose of an earlier formulation of ProQuad was comparable to the immunogenicity of a single dose of its individual component vaccines (Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by MSD), currently used in routine vaccination in some countries.

Clinical trials involving 6987 subjects who received ProQuad demonstrated detectable immune responses to measles, mumps, rubella, and varicella in a high proportion of individuals. The presence of detectable antibody was assessed by an appropriately sensitive enzyme-linked immunosorbent assay (ELISA) for measles, mumps (wild-type and vaccine-type strains), and rubella, and by gpELISA for varicella.
Following a single dose of ProQuad, the vaccine response rates were 97.7% for measles, 96.3% to 98.8% for mumps, and 98.8% for rubella. While the seroconversion rate for varicella was uniformly high (97.9% to 99.8% across all studies), seroconversion has not been shown to correlate well with protection. The vaccine response rate was 90.9% (range 80.8% to 94.5%) for varicella based on a post-vaccination antibody titre ≥5 gpELISA units/mL (an antibody titre that has been shown to be highly correlated with long-term protection). These results were similar to the immune response rates induced by concomitant administration of a single dose of Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by MSD at separate injection sites.

Evaluation of immunogenicity in children from 9 to 12 months of age at the time of first dose A clinical study was conducted with ProQuad administered with a 2-dose schedule, the doses being given 3 months apart in 1,620 healthy subjects from 9 to 12 months of age at the time of first dose. The safety profile post-dose 1 and 2 was generally comparable for all age cohorts.

In the Full Analysis Set (vaccinated subjects regardless of their antibody titre at baseline), high seroprotection rates of >99% were elicited to mumps, rubella, and varicella post-dose 2, regardless of the age of the vaccinees at the first dose. After 2 doses, the seroprotection rates against measles were 98.1% when the first dose was given at 11 months, compared to 98.9% when the first dose was given at 12 months (non-inferiority study objective met). After two doses, the seroprotection rates against measles were 94.6% when the first dose was given at 9 months, compared to 98.9% when the first dose was given at 12 months (non-inferiority study objective not met).

The seroprotection rates to measles, mumps, rubella, and varicella 6 weeks post-dose 1 and 6 weeks post-dose 2, for the Full Analysis Set are given in the following table.


Dose 1 at 9 months /      Dose 1 at 11 months /      Dose 1 at 12 months / Valence
Dose 2 at 12 months       Dose 2 at 14 months        Dose 2 at 15 months (seropro      Time
N = 527                   N = 480                    N = 466 tection      point
Seroprotection rates      Seroprotection rates       Seroprotection rates level)
[95% CI]                  [95% CI]                   [95% CI]
Post-             72.3%                      87.6%                     90.6% Measles dose 1          [68.2; 76.1]               [84.2; 90.4]              [87.6; 93.1] (titre ≥255
Post-             94.6%                      98.1%                     98.9% mIU/mL) dose 2          [92.3; 96.4]               [96.4; 99.1]              [97.5; 99.6] Mumps        Post-             96.4%                      98.7%                     98.5% (titre ≥10    dose 1          [94.4; 97.8]               [97.3; 99.5]              [96.9; 99.4] ELISA Ab      Post-             99.2%                      99.6%                     99.3% units/mL)     dose 2          [98.0; 99.8]               [98.5; 99.9]              [98.1; 99.9] Post-             97.3%                      98.7%                     97.8% dose 1          [95.5; 98.5]               [97.3; 99.5]              [96.0; 98.9] 

Rubella                         99.4%                      99.4%                       99.6% (titre ≥10    Post-           [98.3; 99.9]               [98.1; 99.9]                [98.4; 99.9] IU/mL)       dose 2

Varicella      Post-             93.1%                      97.0%                       96.5% (titre ≥5 gp   dose 1          [90.6; 95.1]               [95.1; 98.4]                [94.4; 98.0] ELISA          Post-             100%                        100%                       100% units/mL)      dose 2          [99.3; 100]                 [99.2; 100]                [99.2; 100] 

The post-dose 2 geometric mean titres (GMTs) against mumps, rubella, and varicella were comparable across all age categories, while the GMTs against measles were lower in subjects who received the first dose at 9 months of age as compared to subjects who received the first dose at 11 or 12 months of age.

Children who received a second dose of ProQuad
In 2 clinical trials, 1035 subjects were administered a second dose of ProQuad approximately 3 months after the first dose. The vaccine response rates were 99.4% for measles, 99.9% for mumps, 98.3% for rubella, and 99.4% for varicella (≥5 gpELISA Units/mL). The geometric mean titres (GMTs) following the second dose of ProQuad increased approximately 2 fold each for measles, mumps, and rubella, and approximately 41 fold for varicella (for safety information, see section 4.8).

Children who received 2 doses of ProQuad intramuscularly or subcutaneously In a clinical trial, 405 children received 2 doses of ProQuad, either by the intramuscular or subcutaneous route of administration. Two doses of ProQuad administered by the IM route of administration were as immunogenic as two doses administered by the SC route in terms of antibody response rates and antibody titres to measles, mumps, rubella, and varicella.

Children who received ProQuad at 4 through 6 years of age after primary vaccination with Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by MSD The immunogenicity and safety of ProQuad were evaluated in a clinical trial involving 799 subjects 4 through 6 years of age who had received Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by MSD at least 1 month prior to study entry. Following the dose of ProQuad, GMTs for measles, mumps, rubella, and varicella were similar to those following a second dose of Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by MSD administered concomitantly at separate injection sites. Additionally, GMTs for measles, mumps, and rubella were similar to those following a second dose of the measles, mumps, and rubella vaccine manufactured by MSD given concomitantly with placebo (for safety information, see section 4.8).

Persistence of immune response
The persistence of antibody at 1 year after vaccination was evaluated in a subset of 2108 subjects who were involved in 1 clinical trial. The antibody persistence rates 1 year postvaccination in recipients of a single dose of ProQuad were 98.9% (1722/1741) for measles, 96.7% (1676/1733) for mumps, 99.6% (1796/1804) for rubella, and 97.5% (1512/1550) for varicella (≥5 gpELISA Units/mL).

Experience with the measles, mumps, and rubella vaccine manufactured by MSD demonstrates that antibodies to measles, mumps, and rubella viruses are still detectable in most individuals 11 to 13 years after primary vaccination. In clinical studies involving healthy subjects who received 1 dose of Varicella Vaccine live (Oka/Merck), detectable varicella antibodies were present in most individuals tested for up to 10 years postvaccination.

Observational studies of long-term effectiveness of varicella vaccine 
Surveillance data from two U.S. observational effectiveness studies confirmed that widespread varicella vaccination reduces the risk of varicella by approximately 90% and that protection is maintained over at least 15 years both in vaccinated and unvaccinated individuals. These data also suggest that varicella vaccination may reduce the risk of herpes zoster in vaccinated individuals.

In the first study, a long-term prospective cohort study, approximately 7,600 children vaccinated in 1995 with varicella vaccine in their second year of life were actively followed for 14 years in order to estimate the occurrence of varicella and herpes zoster. Over the entire follow-up, the incidence of varicella was approximately 10-fold lower among vaccinees than among children of the same age in the pre-vaccine era (estimated vaccine effectiveness over the study period was between 73% and 90%). Regarding herpes zoster, there were fewer herpes zoster cases among varicella vaccinees during the follow-up period than expected from rates in children of the same age with prior wild-type varicella during the pre-vaccine era (relative risk = 0.61, 95% CI 0.43 - 0.89). Breakthrough varicella and zoster cases were usually mild.

In a second long-term surveillance study, five cross-sectional surveys on varicella incidence, each from a random sample of approximately 8,000 children and adolescents 5 to 19 years of age, were conducted over 15 years, from 1995 (pre-vaccine) through 2009. Results showed a gradual decline of varicella rates by an overall 90% to 95% (approximately 10- to 20-fold) from 1995 to 2009 in all age groups, both in vaccinated and unvaccinated children and adolescents. In addition, a decrease by approximately 90% (approximately 10-fold) in varicella hospitalisation rates was observed in all age groups.

Post-marketing observational safety surveillance study
Safety was evaluated in an observational study that included 69,237 children vaccinated with ProQuad 12 months to 12 years old and 69,237 matched children in a historical comparison group who were vaccinated concomitantly with the measles, mumps, and rubella vaccine manufactured by MSD, and the Varicella Vaccine live (Oka/Merck). In addition to assessing the incidence of febrile seizures occurring within 30 days after the first dose (see section 4.8), the study also assessed the general safety of ProQuad in the 30-day period after the first or second dose. Other than the increase in febrile seizure after the first dose, no safety concerns after the first or second dose were identified.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Not applicable.