Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1           Pharmacodynamic properties
Pharmacotherapeutic group: Influenza vaccine, ATC code: J07BB02.
Annual influenza vaccination is recommended because immunity during the year after vaccination declines and because circulating strains of influenza virus change from year to year.

Pharmacodynamic effects

Immunogenicity - QHD00013
A randomized, active-controlled, modified double-blind Phase III clinical trial was conducted in the US in adults 65 years and older.

The objective was to demonstrate the noninferiority of Efluelda over TIV-HD, as assessed by HAI (hemagglutinin inhibition) Geometric mean antibody titers (GMTs) at Day 28 and seroconversion rates.

A total of 2670 adults from 65 years of age were randomized to receive either one dose of Efluelda or one dose of TIV-HD (one of two formulations of comparator vaccine [TIV-HD1 or TIV-HD2]); each TIV HD formulation contained a B strain that corresponds to one of the two B strains in Efluelda (either a B strain of the Yamagata lineage or a B strain of the Victoria lineage).

The immunogenicity results are summarized below in
Table 1.
Table 1: Study 1a: Analyses of Noninferiority of Efluelda Relative to TIV-HD by Post-Vaccination HAI Antibody GMTs and Seroconversion Rates in Adults 65 Years of Age and Older, Per-Protocol Analysis Set

GMT                     GMT       Seroconversion Rate (Percentage)b           Difference of Ratio                                                Seroconversion
Rates


QIV-HD       TIV-         TIV-HD2e     QIV-      QIV-HD       TIV-            TIV-HD2e         QIV-HD (Efluelda    HD1d            (B2        HD       (Efluelda    HD1d               (B2          (Efluelda)       Met Pre- Influenza         )        (B1          Yamagata)     over         )        (B1             Yamagata)         minus          defined Strain                  Victoria)                  TIV-                  Victoria)                         TIV-HD        Noninferiority Nc=430    HD                                         Nc=428     (95% CI)         Criteriaf Nc=1679-     Nc=423                    (95%                    c
N =420-
1680                                  CI)                    421
(95% CI)              Nc=1668-                      (95% CI)
(95%                                 1669
(95%         CI)                                            (95%
CI)                                                         CI)
(95%
CI)
312                                 0.83       50.4
374                                                 53.7                -3.27 A (H1N1) g      (292;                                 (0.744;    (48.0;                                                          Yes (341; 411)        0.932)
(50.2; 57.1)         (-7.37; 0.86)
332)                                            52.8)
563                                 0.95       49.8
594                                                 50.5                -0.71 A (H3N2) g      (525;                                 (0.842;    (47.3;                                                          Yes (540; 653)        1.066)
(47.1; 53.9)         (-4.83; 3.42)
603)                                            52.2)
516        476                      1.08       36.5        39.0
B1                                                                                                             -2.41 (Victoria)      (488;        (426;             --     (0.958;    (34.2;      (34.3;                 --                           Yes (-7.66; 2.70)
545)         532)                    1.224)     38.9)       43.8)
578                                 1.00       46.6                             48.4 B2                                            580                                                              -1.75 (547;          --                     (0.881;    (44.2;           --              (43.5;                         Yes (Yamagata)                               (519; 649)                                                         (-7.04; 3.53) 612)                                 1.129)     49.0)                            53.2) a NCT03282240

 b Seroconversion  Rates: For subjects with a pre-vaccination titer <10 (1/dil), proportion of subjects with a post- vaccination titer ≥40 (1/dil) and for subjects with a pre-vaccination titer ≥10 (1/dil), proportion of subjects with a ≥four-fold increase from pre- to post-vaccination titer.
cN  is the number of vaccinated participants with available data for the immunologic endpoint listed d TIV-HD1    contained A/Michigan/45/2015 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Brisbane/60/2008 (B1, Victoria lineage).
e TIV-HD2 contained A/Michigan/45/2015 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Phuket/3073/2013 
(B2, Yamagata lineage).
f Predefined noninferiority criterion for seroconversion rates: the lower limit of the two-sided 95% CI of the  difference of the seroconversion rates (Efluelda minus TIV-HD) is >-10%. Predefined noninferiority criterion for the GMT ratio: the lower limit of the 95% CI of the GMT ratio (Efluelda divided by TIV-HD) is >0.667.
g For the A strain comparison, TIV-HD1 and TIV-HD2 were pooled into a TIV-HD group for comparison with 
Efluelda.

Efluelda was as immunogenic as TIV-HD for GMTs and seroconversion rates for the common influenza strains. Moreover, Efluelda induced a superior immune response with respect to the additional B strain than the immune response induced by TIV-HD that does not contain the corresponding B.
The efficacy and effectiveness results of TIV-HD are thus inferred to Efluelda given the demonstration of statistically comparable immunogenicity between TIV-HD and Efluelda in the QHD00013 study.

QHD00011

A randomized, active-controlled, modified double-blind, Phase III clinical trial conducted in Europe in adults 60 years and older to demonstrate the superiority of Quadrivalent Influenza Vaccine (Split Virion, Inactivated) High‫כ‬Dose over QIV-SD for all strains, as assessed by HAI (hemagglutinin inhibition) geometric mean antibody titers (GMTs) at Day 28 in adults 60 to 64 years of age and in adults 65 years of age and older.

A total of 1539 adults (760 adults 60 to 64 years of age and 779 adults 65 years of age and older) were randomized to receive either one dose of Quadrivalent Influenza Vaccine (Split Virion, Inactivated) High‫כ‬Dose or one dose of QIV-SD.
Table 2: Study 2a: Analyses of Superiority of Quadrivalent Influenza Vaccine (Split Virion, Inactivated) HighDDose Relative to QIV-SD by Post-Vaccination HAI Antibody GMTs in Adults 60-64 Years of Age and 65 Years of Age and Older, Full Analysis Set Adults 60 to 64 Years of Age                       Adults 65 years of Age and Older

GMT             GMT        Met Pre-               GMT            GMT defined                                          Met Pre-
Ratio                                            Ratio
Influenza                                         Superiority                                         defined Strain                                           Criteriac                                        Superiority QIV-HD      QIV-SD       QIV-HD                   QIV-HD       QIV-SD      QIV-HD      Criteriac Nb=377         over                               Nb=381         over Nb=376-     (95%         QIV-SD                   Nb=392     (95% CI)     QIV-SD 377        CI)        (95% CI)                 (95% CI)                  (95% (95% CI)                                                                     CI) 286            162      1.76
471            248      1.90
Yes         (250 ;         (139 ;   (1.44 ;
A (H1N1)        (416 ;         (217 ;   (1.58 ;                                                         Yes 326)           190)     2.15)
533)           283)     2.28)

303            178      1.70                      324            151      2.15 A (H3N2)        (262 ;         (154 ;   (1.38 ;       Yes         (281 ;         (129 ;   (1.74 ;       Yes 350)           206)     2.08)                     374)           176)     2.65) 
497                                                                       1.55
330      1.51                      405            262
B1                                                    Yes                                 (1.34 ; (Victoria)
(450 ;         (297 ;   (1.30 ;                   (366 ;         (236 ;                 Yes 1.79)
548)           367)     1.74)                     447)           291) 
766                                                                       1.76 433      1.77                      536            305
B2                                                    Yes                                 (1.52 ; (Yamagata)
(690 ;         (391 ;   (1.53 ;                   (485 ;         (274 ;                 Yes 2.03)
849)           480)     2.04)                     592)           340) a NCT04024228 bN is the number of participants with available data for the considered endpoint cSuperiority was concluded if the lower limit of the two-sided 95% CI of the ratio of GMTs between groups (QIV- HD/QIV-SD) was > 1 for each strain and in each age group

The efficacy and effectiveness results of TIV-HD are thus inferred to Quadrivalent Influenza Vaccine (Split Virion, Inactivated) High‫כ‬Dose, given the demonstration of statistically comparable immunogenicity between TIV-HD and Quadrivalent Influenza Vaccine (Split Virion, Inactivated) High‫כ‬Dose in adults 65 years of age and older (QHD00013) and similar immune responses observed in adults 60 to 64 years of age and in adults 65 years of age and older (QHD00011).

In addition, Quadrivalent Influenza Vaccine (Split Virion, Inactivated) High‫כ‬Dose induced an immune response that was superior to the responses induced by QIV-SD for all 4 virus strains 28 days post-vaccination in adults 60 to 64 years of age and in adults 65 years of age and older.

Pivotal Clinical Efficacy (FIM12)
FIM12 was a multi-centre, double-blind efficacy trial conducted in the US and Canada in which adults 65 years of age and older were randomised (1:1) to receive the TIV-HD or a standard dose vaccine. The study was conducted over two influenza seasons (2011-2012 and 2012-2013) to assess the occurrence of laboratory-confirmed influenza caused by any influenza viral type/subtype, in association with influenza-like illness (ILI) as the primary endpoint.

Participants were monitored for the occurrence of a respiratory illness by both active and passive surveillance, starting 2 weeks post-vaccination for approximately 7 months. After an episode of respiratory illness, nasopharyngeal swab samples were collected for analysis; attack rates and vaccine efficacy were calculated. The pre-specified statistical superiority criterion for the primary endpoint (lower limit of the 2-sided 95% CI of the vaccine efficacy for the TIV-HD relative to standard dose vaccine > 9.1%) was met.


Table 3: Relative vaccine efficacy to prevent influenza-like illnessa in adults ≥ 65 years Standard dose                   Relative
High Dose vaccine                    vaccine                      Efficacy Nb=15892                         Nb=15911                     % (95% CI) nc (%)                           nc (%)
Laboratory-confirmed influenzad caused by:
- Any type/subtypee                      227 (1.43)                      300 (1.89)                24.2 (9.7; 36.5) - Viral strains similar to those                        73 (0.46)                      113 (0.71)                35.3 (12.4; 52.5) contained in the vaccine aOccurrence of at least one of the following respiratory symptoms: sore throat, cough, sputum production, wheezing,  or difficulty breathing; concurrent with at least one of the following systemic signs or symptoms: temperature >37.2°C, chills, tiredness, headaches or myalgia bN   is the number of vaccinated participants in the per-protocol analysis set for efficacy assessments cn   is the number of participants with protocol-defined influenza-like illness with laboratory confirmation dLaboratory-confirmed:     culture- or polymerase-chain-reaction-confirmed ePrimary   endpoint


Effectiveness Studies
Randomized Clinical Trials
A cluster-randomized, controlled clinical trial in United States nursing homes assessed the relative effect of TIV-HD versus a standard dose of influenza vaccine in hospitalizations among 53008 individuals during the 2013-2014 influenza season.

During the 2013-2014 season, the incidence of respiratory-related hospital admissions (primary objective) was significantly reduced in facilities where residents received TIV-HD compared with those that received standard-dose influenza vaccines by 12.7% (adjusted risk ratio [ARR] 0.873, 95% CI 0.776 to 0.982, p=0.023). Moreover, with respect to secondary endpoints, TIV-HD reduced hospital admissions for pneumonia by 20.9% (ARR 0.791, 95% CI: 0.267 to 0.953, p=0.013) and all-cause hospital admissions by 8% (ARR 0.915, 95% CI: 0.863 to 0.970, p=0.0028).

Observational Studies
Several retrospective studies, over 8 influenza seasons and in more than 24 million individuals 65 years of age and older, confirmed the superior protection offered by TIV-HD compared to standard-dose influenza vaccines against complications of influenza such as pneumonia and influenza hospitalization (13.4% (95%CI: 7.3% to 19.2%, p<0.001)), cardio-respiratory hospitalizations 17.9% (95%CI :14.9% to 20.9%, p<0.001) and all –cause hospitalization 8.1% (95%CI: 5.9% to 10.3%, p<0.001) ; although the impact may vary per season.

Concomitant Administration with COVID-19 mRNA Vaccine (nucleoside modified) 
In a descriptive open-label clinical study (NCT04969276), healthy adults aged 65 years and older were divided in three groups: Group 1 received Efluelda alone (N=92), Group 2 (N=100) received Efluelda concomitantly with an investigational booster 100 mcg dose of COVID-19 mRNA vaccine (nucleoside modified) at least 5 months after the second dose of the primary series, Group 3 (N=104) received only the investigational booster 100 mcg dose of COVID-19 mRNA vaccine (nucleoside modified).

Co-administration resulted in no change to influenza vaccine immune responses as measured by hemagglutination inhibition (HAI) assay. Co-administration resulted in similar responses to COVID-19 mRNA vaccine, as assessed by an anti-spike IgG assay (see section 4.5 and 4.8).

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

Not applicable.