Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Influenza vaccine, ATC Code: J07BB02
Mechanism of action

Fluarix Tetra provides active immunisation against four influenza virus strains (two A subtypes and two B lineages ) contained in the vaccine.

Fluarix Tetra induces humoral antibodies against the haemagglutinins. These antibodies neutralise influenza viruses.

Specific levels of haemagglutination-inhibition (HI) antibody titre post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the HI antibody titres have been used as a measure of vaccine activity. In some human challenge studies, HI antibody titres of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.

Pharmacodynamic effects

Efficacy in children 6-35 months of age:
The efficacy of Fluarix Tetra was evaluated in clinical study D-QIV-004, a randomised, observer- blind, non-influenza vaccine-controlled trial conducted during influenza seasons 2011 to 2014.
Healthy subjects aged 6 through 35 months were randomized (1:1) to receive Fluarix Tetra (N = 6,006) or a non-influenza control vaccine (N = 6,012). They were administered 1 dose (in case of history of influenza vaccination) or 2 doses, approximately 28 days apart.

Efficacy of Fluarix Tetra was assessed for the prevention of reverse transcription polymerase chain reaction (RT-PCR)-confirmed influenza A and/or B disease (moderate to severe and of any severity) due to any seasonal influenza strain. Starting 2 weeks post-vaccination until the end of the influenza season (approximately 6 months later), nasal swabs were collected following an influenza like event, and tested for influenza A and/or B by RT-PCR. All RT-PCR-positive specimens were further tested for viability in cell culture and to determine whether the viral strains matched those in the vaccine.

Fluarix Tetra met the predefined criteria for primary and secondary vaccine efficacy objectives presented in Table 1.

Table 1: Fluarix Tetra: Attack rates and vaccine efficacy in children 6-35 months of age (ATP (according to protocol) cohort for efficacy – time to event)


Fluarix Tetra                  Active comparator1       Vaccine efficacy 
N2       n3     Attack         N2     n3   Attack       %       CI rate                       rate
(n/N)                      (n/N) (%)
(%)
Any severity Influenza6
RT-PCR confirmed                  5,707 344 6.03             5,697 662 11.62              49.8 41.8; 56.84 Culture confirmed                 5,707 303 5.31             5,697 602 10.57              51.2 44.1; 57.65 Culture confirmed vaccine         5,707 88     1.54          5,697 216 3.79               60.1 49.1; 69.05 matching strains
Moderate to Severe Influenza7
RT-PCR confirmed                  5,707 90     1.58          5,697 242 4.25               63.2 51.8; 72.34 Culture confirmed                 5,707 79     1.38          5,697 216 3.79               63.8 53.4; 72.25 Culture confirmed vaccine         5,707 20     0.35          5,697 88       1.54          77.6 64.3; 86.65 matching strains
Lower respiratory Illness         5,707 28     0.49          5,697 61       1.07          54.0 28.9; 71.05 RT-PCR Confirmed
Acute Otitis media RT PCR- 5,707 12            0.21          5,697 28       0.49          56.6 16.7; 78.85 confirmed
CI: Confidence Interval
1
Children received age appropriate non-influenza vaccine control
2
Number of subjects included in the ATP cohort for efficacy - time to event. This cohort included subjects who met all eligibility criteria, who were followed for efficacy and complied with the study protocol until the episode.
3
Number of subjects who reported at least one case in the reporting period 4
Two-sided 97.5% confidence interval
5
Two-sided 95% confidence interval
6
Influenza disease of any severity was defined as an episode of influenza-like illness (ILI, i.e. fever ≥38°C with any of the following: cough, runny nose, nasal congestion, or breathing difficulty) or a consequence of influenza virus infection [acute otitis media (AOM) or lower respiratory illness (LRI)].
7
Moderate to severe influenza was a subset of any influenza disease, with any of the following: fever >39°C, physician-diagnosed AOM, physician-diagnosed lower respiratory tract infection, physician-diagnosed serious extra-pulmonary complications, hospitalisation in the intensive care unit, or supplemental oxygen required for more than 8 hours.


Exploratory analyses were conducted on the Total Vaccinated Cohort including 12,018 subjects (N = 6,006 for Fluarix Tetra, N = 6,012 for control). Fluarix Tetra was efficacious in the prevention of moderate to severe influenza caused by each of the 4 strains (Table 2), even when there was significant antigenic mismatch with 2 of the vaccine strains (A/H3N2 and B/Victoria).
Table 2: Fluarix Tetra: Attack rates and vaccine efficacy for RT-PCR confirmed moderate to severe disease by Influenza A subtypes and Influenza B lineages in children 6-35 months of age (Total Vaccinated Cohort)

Fluarix Tetra                   Active comparator1                 Vaccine Efficacy Strain         N2       n3     Attack rate     N2        n3        Attack rate    %            95% CI (n/N) (%)                           (n/N) (%)
A
H1N14          6,006     13        0.22         6,012         46       0.77           72.1     49.9; 85.5 5
H3N2           6,006     53        0.88         6,012     112          1.86           52.7     34.8; 66.1 B
Victoria6        6,006      3        0.05         6,012     15         0.25         80.1     39.7; 95.4 7
Yamagata         6,006     22        0.37         6,012     73         1.21         70.1     52.7; 81.9 CI: Confidence Interval
1
Infants received age appropriate non-influenza vaccine control
2
Number of subjects included in the Total Vaccinated cohort
3
Number of subjects who reported at least one case in the reporting period 4 to 7
Proportion of antigenic matching strains was 84.8%, 2.6%, 14.3% and 66.6%, for A/H1N1, A/H3N2, B/Victoria, and B/Yamagata, respectively.

Additionally, for RT-PCR confirmed cases of any severity, Fluarix Tetra reduced the risk of visits to the general practitioner by 47% (Relative Risk (RR): 0.53 [95% CI: 0.46; 0.61], i.e., 310 versus 583 visits) and to the emergency room by 79% (RR: 0.21 [95% CI: 0.09; 0.47], i.e., 7 versus 33 visits).
The use of antibiotics was reduced by 50% (RR: 0.50 [95% CI: 0.42; 0.60], i.e., 172 versus 341 subjects).


Efficacy in adults 18-64 years of age
A clinical study performed in more than 7,600 subjects in the Czech Republic and Finland evaluated the efficacy of Fluarix to prevent culture-confirmed influenza A and/or B cases for vaccine antigenically matched strains.

Subjects were monitored for influenza-like illness to be confirmed by culture (see table 3 for results). Influenza-like illness was defined as at least one general symptom (fever ≥37.8°C and/or myalgia) and at least one respiratory symptom (cough and/or sore throat).


Table 3: Attack rates and Vaccine Efficacy against Illness associated with evidence of influenza A or B Infection in adults 18 to 64 years of age (Total Vaccinated Cohort) 
Attack Rates (n/N)1              Vaccine Efficacy (95%
CI2)
N         n                %                              %       LL3        UL4 Antigenically matched, culture-confirmed Influenza5
Fluarix         5,103      49               1.0             66.9                      51.9      77.4 Placebo         2,549      74               2.9              -                         -         - All culture-confirmed Influenza (Matched, Unmatched and Untyped)6
Fluarix         5,103      63               1.2             61.6                      46.0      72.8 Placebo         2,549      82               3.2              -                         -         - 1 n/N: number of case/total number of subjects
2
CI: Confidence Interval
3
LL: Lower Limit
4
UL: Upper Limit
5
There were no vaccine matched culture-confirmed cases of A/New Caledonia/20/1999 (H1N1) or B/Malaysia/2506/2004 influenza strains with Fluarix or placebo
6
Of the 22 additional cases, 18 were unmatched and 4 were untyped; 15 of the 22 cases were A (H3N2) (11 cases with Fluarix and 4 cases with placebo).

In this study, immunogenicity was also evaluated.

Table 4: Post-vaccination GMT and seroconversion rates
Adults 18 years to 64 years                               Fluarix1
N=291
GMT (95% CI)
A/H1N1                                                      541.0 (451.0;649.0) A/H3N2                                                      133.2 (114.6;154.7) B (Victoria)                                                242.8 (210.7;279.7) Seroconversion rate (95% CI)
A/H1N1                                                       76.3% (71.0;81.1) A/H3N2                                                       73.9% (68.4;78.8) B (Victoria)                                                 85.2% (80.6;89.1) CI: Confidence Interval
1 containing A/H1N1, A/H3N2 and B (Victoria lineage)

Post-vaccination seroprotection rates were 97.6% against A/H1N1, 86.9% against A/H3N2 and 96.2% against B (Victoria).


Immunogenicity in children and adults:
Immunogenicity of Fluarix Tetra was evaluated in terms of HI Geometric mean antibody titre (GMT) at 28 days after the last dose (children) or Day 21 (adults) and HI seroconversion rate (4- fold rise in reciprocal titre or change from undetectable [< 10] to a reciprocal titre of ≥ 40).

In study D-QIV-004 (children 6-35 months), the evaluation was performed in a sub-cohort of 1,332 children (753 in the Fluarix Tetra group and 579 in the control group). The results are presented in Table 5.

The effect of a 2-dose priming schedule in D-QIV-004 was evaluated by assessing the immune response after revaccination one year later with 1 dose of Fluarix Tetra in study D-QIV-009. This study demonstrated that 7 days post-vaccination, immune memory in children 6 to 35 months of age had been elicited for all four vaccine strains.

Immunogenic non-inferiority of Fluarix Tetra was assessed versus Fluarix in children in study D- QIV-003 (approximately 900 children 3 to < 18 years of age in each treatment group who received one or two doses of either vaccine) and adults in study D-QIV-008 (approximately 1,800 subjects 18 years of age and older received 1 dose of Fluarix Tetra and approximately 600 subjects received 1 dose of Fluarix). In both studies, Fluarix Tetra elicited an immune response against the three strains in common that was non-inferior to Fluarix and a superior immune response against the additional B strain included in Fluarix Tetra. The results are presented in Table 5.
Table 5: Fluarix Tetra: Post-vaccination GMT and seroconversion rates (SCR) in children (6- 35 months; 3 to < 18 years) and adults 18 years or older (According to Protocol Cohort) 
Children 6 to 35 months (D-QIV-004)
Fluarix Tetra                                     Control1
N=750-753          N’=742-746                 N=578-579           N’=566-568 GMT2 (95% CI) Seroconversion rate2             GMT2 (95% CI)       Seroconversion (95% CI)                                          rate2
(95% CI)
A/H1N1                   165.3           80.2% (77.2;83.0)       12.6 (11.1;14.3)     3.5% (2.2;5.4) (148.6;183.8)
A/H3N2                   132.1           68.8% (65.3;72.1)        14.7 (12.9;16.7)        4.2% (2.7;6.2) (119.1;146.5)
B (Victoria)       92.6 (82.3;104.1)     69.3% (65.8;72.6)         9.2 (8.4;10.1)         0.9% (0.3;2.0) B (Yamagata)             121.4           81.2% (78.2;84.0)          7.6 (7.0;8.3)         2.3% (1.2;3.9) (110.1;133.8)
Children 3 to < 18 years (D-QIV-003)
Fluarix Tetra                                      Fluarix3
N=791                 N’=790               N=818                      N’=818 GMT (95% CI)       Seroconversion rate       GMT (95% CI)             Seroconversion (95% CI)                                           rate
(95% CI)
A/H1N1                    386.2          91.4% (89.2;93.3)             433.2             89.9% (87.6;91.8) (357.3;417.4)                                 (401.0;468.0)
A/H3N2                    228.8          72.3% (69.0;75.4)             227.3             70.7% (67.4;73.8) (215.0;243.4)                                 (213.3;242.3)
B (Victoria)              244.2          70.0% (66.7;73.2)             245.6             68.5% (65.2;71.6) (227.5;262.1)                                 (229.2;263.2)
B (Yamagata)              569.6          72.5% (69.3;75.6)             224.7             37.0% (33.7;40.5) (533.6;608.1)                                 (207.9;242.9)
Adults 18 years or older (D-QIV-008)
Fluarix Tetra                                      Fluarix3
N=1,809              N’=1,801              N=608                      N’=605 GMT (95% CI)       Seroconversion rate       GMT (95% CI)             Seroconversion (95% CI)                                           rate
(95% CI)
A/H1N1                    201.1             77.5% (75.5;79.4)            218.4           77.2% (73.6;80.5) (188.1;215.1)                                 (194.2;245.6)
A/H3N2                  314.7             71.5% (69.3;73.5)            298.2         65.8% (61.9;69.6) (296.8;333.6)                                 (268.4;331.3)
B (Victoria)            404.6             58.1% (55.8;60.4)            393.8         55.4% (51.3;59.4) (386.6;423.4)                                 (362.7;427.6)
B (Yamagata)            601.8             61.7% (59.5;64.0)            386.6         45.6% (41.6;49.7) (573.3;631.6)                                 (351.5;425.3)
CI: Confidence Interval
N = Number of subjects with post-vaccination results available (for GMT) N’ = Number of subjects with both pre- and post-vaccination results available (for SCR) 1 non-influenza vaccine control
2 results from the immunogenicity subcohort
3
B (Yamagata) strain was not included in Fluarix

Concomitant administration with pneumococcal polysaccharide vaccines: 
In clinical study D-QIV-010 involving 356 adults ≥50 years of age at risk for complications of influenza and pneumococcal diseases, subjects received Fluarix Tetra and 23-valent pneumococcal polysaccharide vaccine (PPV23) either concomitantly or separately. For all four Fluarix Tetra vaccine strains and the six pneumococcal serotypes (1, 3, 4, 7F, 14, and 19A) in PPV23 evaluated in the pre-specified primary analysis, the immune response was non-inferior between the two treatment groups. Based on a descriptive analysis for six additional pneumococcal vaccine serotypes (5, 6B, 9V, 18C, 19F, and 23F), the immune response was comparable between groups, with 91.7% to 100% and 90.7% to 100% of subjects attaining seroprotective antibody levels against these serotypes in the separate and concomitant administration group respectively.

Concomitant administration with adjuvanted herpes zoster vaccine (Shingrix): 
In clinical study Zoster-004, 828 adults ≥ 50 years of age were randomised to receive 2 doses of Shingrix 2 months apart, administered either concomitantly at the first dose (N=413) or non- concomitantly (N=415) with one dose of Fluarix Tetra. The antibody responses to each vaccine were similar, whether administered concomitantly or non-concomitantly. Furthermore, immunological non-inferiority between concomitant and non-concomitant administration was demonstrated for all four strains included in Fluarix Tetra in terms of HI antibody GMTs.

Concomitant administration with COVID-19 mRNA vaccine:

In clinical study Zoster-091, 988 adults ≥ 18 years of age received Fluarix Tetra and monovalent COVID-19 mRNA-1273 booster (50 micrograms) vaccine (original SARS-CoV-2 strain) either concomitantly (N=498) or non-concomitantly, administered two weeks apart (N=490). The antibody responses to each vaccine were similar, regardless of administration schedule. Immunological non- inferiority between concomitant and non-concomitant administration was demonstrated for all four strains included in Fluarix Tetra in terms of HI antibody GMTs, and for the COVID-19 mRNA- 1273 booster vaccine in terms of anti-S protein antibody GMC.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Not applicable.