Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccine, ATC code: J07BB02
The immune response of Fluad has been evaluated in 16 randomized controlled trials including 16.974 subject vaccinated with Fluad (n=5869) or a non-adjuvanted vaccine (n=5236).

Seroprotection is generally obtained within 2 to 3 weeks. The duration of post vaccination immunity to homologous strains or to strains closely related to the vaccine strains varies, but it is usually 6-12 months.

Although comparative field efficacy trials have not been performed, the antibody response to Fluad is increased when compared to the response to vaccines without adjuvant, and is most pronounced for B and A/H3N2 influenza antigens.

This increased response is seen particularly in elderly subjects with low pre-immunisation titre and/or with underlying diseases (diabetes, cardiovascular and respiratory diseases) who are at increased risk of complications of influenza infection. A similar immunogenicity profile has been noted after a second and third immunisation with Fluad.
Significant antibody rises after immunisation with Fluad have also been shown against heterovariant strains, antigenically different from those included in the vaccine.

The clinical effectiveness of Fluad has been evaluated in two observational studies: 
Observational studies:

The first study (Study C70P1) was an observational prospective cohort study performed in 5 Northern Italian health districts during the 2006-7, 2007-8 and 2008-9 influenza seasons. The study objective was to assess the relative risk of hospitalizations for influenza or pneumonia during the influenza season amongst subjects 65 years of age or older who received either Fluad or a non-adjuvanted vaccine. The choice of influenza vaccine for each study subject, either Fluad or a non-adjuvanted vaccine, was left to the individual provider to be determined on the basis of local influenza vaccination policy. This multi-year study enrolled 107,661 elderly subjects, 65 years of age or older, with 43,667 subjects participating for more than 1 year.
In total, 88,449 doses of Fluad and 82,539 doses of non-adjuvanted vaccine were administered. Predefined windows during the influenza season were used to determine the primary endpoint of hospitalization due to influenza or pneumonia, but laboratory based confirmation of influenza was not performed. Due to local immunization policy, subjects who received Fluad often had worse baseline health status than those subjects who received a non-adjuvanted vaccine. After adjusting for confounding variables (baseline health status, others), the risk of hospitalization for influenza or pneumonia was 25% lower for Fluad relative to non- adjuvanted vaccine (relative risk = 0.75, 95% confidence interval: 0.57, 0.98).

The second study (study V70-49OBTP) was a retrospective case-control study evaluating vaccine effectiveness of Fluad, a non-adjuvanted comparator, or no vaccination. Cases and controls were identified from the influenza tests performed in the population served by three main health authorities in British Columbia and analysed at a central provincial laboratory. In total 84 cases and 198 controls of 65 years of age or older were enrolled (165 vaccinated with Fluad, 62 with a non-adjuvanted influenza vaccine and 55 unvaccinated subjects). The majority of the participants reported at least one chronic disease (89%). The most commonly reported chronic disease categories were cardiac (72%) followed by neurological (39%) and respiratory condition (30%). Cases were defined as RT-PCR confirmed influenza following onset of influenza-like illness (ILI). Controls were individuals with similar characteristics, but who tested negative for influenza. After adjusting for confounding variables (age, sex, residency in a long-term care facility, chronic conditions, region and week of testing), the absolute vaccine effectiveness for Fluad was 58% (CI: 5-82, p<0.04) and non-adjuvanted vaccine was ineffective. The relative vaccine effectiveness for Fluad was 63% (CI: 4-86. P=0.04) as compared to non-adjuvanted influenza vaccine.

Randomized controlled interventional studies:

Study V70-27-01 is a large Phase 3, randomized, controlled, observer-blind, multicenter study to evaluate the immunogenicity, the safety and the consistency of three consecutive lots of Fluad in comparison to non- adjuvanted vaccine and it was conducted in 2010-2011. Subjects were randomized in a 1:1:1:3 ratio to receive a single 0.5mL dose of 1 of 3 consecutive lots of Fluad or a single lot of a non-adjuvanted influenza vaccine. All subjects were followed for approximately one year post-vaccination.
A total of 7082 subjects were randomized and vaccinated, including 3541 subjects in each of the pooled Fluad and non-adjuvanted vaccine groups. A total of 2573 subjects (1300 in Fluad and 1273 in non- adjuvanted vaccine group) were regarded as “high risk” subjects (underlying chronic diseases including congestive heart failure, chronic obstructive pulmonary disease, asthma, hepatic disease, renal insufficiency and/or neurological/neuromuscular or metabolic disorders including diabetes mellitus).
The primary objective of a superiority of Fluad versus non-adjuvanted vaccine was not achieved for all homologous strains; the co-primary objective of a non-inferiority of Fluad versus non-adjuvanted vaccine was achieved for all homologous strains; however significantly higher HI titers rates against all three homologous strains of influenza at day 22 post vaccination were seen in subjects that received Fluad compared with non-adjuvanted influenza vaccine (Table 1). The results were similar for high risk subjects with predefined comorbidities. Immunogenicity data supported similar antibody responses across Fluad lots; CHMP criteria were met for Fluad.
In addition, in a subset of subjects (n=1649 subjects), Fluad was compared to the non-adjuvanted influenza vaccine for heterologous strains, i.e. influenza variants of the same type/subtype that were not included in the vaccine composition (secondary objective). Superiority of Fluad as compared to non-adjuvanted influenza vaccine was not achieved for all 3 heterologous strains at day 22; however non-inferiority was demonstrated for all 3 heterologous strains at day 22.
Results were similar for high risk subjects (609 subjects).


Table 1:                  Postvaccination GMTs and Vaccine Group Ratios - HI assay Non-adjuvanted
Study      Antigen                Fluad
Vaccine
Vaccine Group
N       GMT (95% CI)           N       GMT (95% CI)
Ratio (95% CI)
All        H3N2      3225            544            3256             337                      1.61 § subjectsa                            (513-575)                       (319-357)               (1.52-1.7) H1N1      3225            198            3257             141                      1.4 §
(185-211)                       (132-150)               (1.32-1.49)
B       3227            55             3259             48                       1.15 §
(52-58)                         (46-51)                (1.08-1.21)
High        H3N2      1194            519            1190             331                      1.57 risk                               (477-565)                       (304-360)                            § (1.44-1.72) subjectsa
H1N1      1194            221            1190             161                      1.38 §
(201-243)                       (146-177)               (1.25-1.52)
B       1195            61             1190             54                       1.12 §
(56-66)                         (50-59)               (1.03-1.21)
HI: Hemagglutination inhibition assay; GMT: Geometric Mean HI titers; CI: Confidence Interval a
Postvaccination (Day 22) GMTs and vaccine group GMT ratios (Fluad: non-adjuvanted influenza vaccine) are adjusted for baseline titer, country and age cohort; Per Protocol Population.
§
As the lower limit of the 95% CI of the vaccine group ratio is greater than 1, it regarded that HI titers after vaccination with Fluad are higher than those of the nonadjuvanted influenza vaccine.


A specific analysis for safety in the “high risk” population was not performed; for the complete population an higher percentage of subjects in the Fluad group than in the non-adjuvanted vaccine reported local reaction (32% vs 17%) and systemic reactions (32% vs 26%). The overall safety profile showed similar incidences of unsolicited AEs and SAEs for Fluad and non-adjuvanted influenza vaccine.

The second study (M63P1) is a phase 3, randomized, active-controlled, observer-blind, multicenter study to evaluate immunogenicity and safety of Fluad in subjects 65 years of age and older with underlying chronic medical conditions. 350 frail elderly subjects were enrolled and randomized 1:1 to receive Fluad (n=175) or non-adjuvanted influenza vaccine (n=175), all of whom had underlying chronic medical conditions including congestive heart failure, chronic obstructive pulmonary disease (COPD) or asthma, hepatic or renal insufficiency, arteriosclerotic disease or diabetes mellitus and rheumatoid arthritis.

The GMT against A/H3N2 influenza strain 21 days after administration of Fluad did not meet the superiority criteria when compared to a non-adjuvanted inactivated split influenza virus vaccine (primary objective). Seroconversion was obtained for 85% (A/H3N2), 87% (A/H1N1) and 88% (B) of subjects.
CHMP criteria for efficacy were met for Fluad.
A small increase in primarily mild local reactogenicity and a slightly higher percentage of systemic reactions were noted for Fluad compared to non-adjuvanted influenza vaccine. The overall safety profile showed similar incidences of unsolicited AEs and SAEs for Fluad and non-adjuvanted influenza vaccine.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Not applicable.