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Pharmacology: Pharmacodynamics: 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. (See Table 1.)
Click on icon to see table/diagram/imageExploratory 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). (See Table 2.)
Click on icon to see table/diagram/imageAdditionally, 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). (See Table 3.)
Click on icon to see table/diagram/imageIn this study, immunogenicity was also evaluated. (See Table 4.)
Click on icon to see table/diagram/imagePost-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 titer (GMT) at 28 days after the last dose (children) or Day 21 (adults) and HI seroconversion rate (4-fold rise in reciprocal titer or change from undetectable [< 10] to a reciprocal titer 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. (See Table 5.)
Click on icon to see table/diagram/imageConcomitant 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.
Pharmacokinetics: Not applicable.
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazards for humans based on conventional studies of acute toxicity, local tolerance, repeated dose toxicity and reproductive/developmental toxicity.
