Fluarix Tetra Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Fluarix Tetra induces haemagglutination-inhibition (HI) antibodies against the 4 influenza virus strains contained in the vaccine. While specific levels of HI antibody in response to inactivated influenza virus vaccines have not been correlated with protection from influenza illness, 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.
Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus might change from year to year.
Pharmacodynamic Effects: Efficacy in children 6-35 months of age: The vaccine efficacy (VE) of Fluarix Tetra was evaluated in 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 randomised (1:1) to receive Fluarix Tetra (N = 6,006) or an age appropriate non-influenza control vaccine (N = 6,012). Subjects were administered 1 dose (in case of history of influenza vaccination) or 2 doses, approximately 28 days apart.
VE of Fluarix Tetra was assessed for the prevention of 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). Fluarix Tetra met the predefined criteria for primary and secondary VE objectives (Table 1). (See Table 1.)

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Exploratory analyses were conducted on the Total Vaccinated Cohort (TVC) including 12,018 subjects. 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.)

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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).
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, the evaluation was performed in a sub-cohort of 1,332 children (Table 3).
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 4 vaccine strains.
Immunogenic non-inferiority of Fluarix Tetra was assessed versus Fluarix in children (study D-QIV-003) and in adults (study D-QIV-008). Children received 1 or 2 doses and adults received 1 dose of either vaccine. In both studies, Fluarix Tetra elicited an immune response against the 3 strains in common that was non-inferior to Fluarix and a superior immune response against the additional B strain included in Fluarix Tetra (Table 3). (See Table 3.)

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Concomitant administration with pneumococcal 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 4 Fluarix Tetra vaccine strains and the 6 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 2 groups. Based on a descriptive analysis for 6 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.
Immunological non-inferiority has been demonstrated based on published data for all 3 Fluarix trivalent strains (D-TIV) and all 13-valent pneumococcal conjugate vaccine (PCV13) serotypes in adults 50-59 years of age, as well as for 2 of 3 D-TIV strains and 12 of 13 PCV13 serotypes in adults >65 years of age. A lower immune response to some pneumococcal serotypes was observed when PCV13 was given concomitantly with D-TIV as compared to separate administration, however the clinical relevance of this observation is unknown.
Toxicology: Non-Clinical Information: 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.