FluQuadri Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Since 2001, two distinct lineages of influenza B (Victoria and Yamagata lineages) have cocirculated worldwide.
Protection from influenza virus infection has not been correlated with a specific level of hemagglutination inhibition (HI) antibody titer post-vaccination. However, in some human studies, antibody titers ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.
Antibodies against one influenza virus type or subtype confer limited or no protection against another. Furthermore, antibodies to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains representing the influenza viruses likely to be circulating in the next season.
Annual vaccination with the current vaccine is recommended because immunity during the year after vaccination declines and because circulating strains of influenza virus change from year to year.
Clinical Studies: Immunogenicity of FluQuadri in Children 6 Months through 8 Years of Age: In a multi-center study conducted in the US, 1419 children 6 months through 35 months of age and 2101 children 3 years through 8 years of age were included in the per-protocol immunogenicity analysis. Participants received one or two 0.25 mL doses or one or two 0.5 mL doses, respectively of FluQuadri, TIV-1, or TIV-2. For participants who received two doses, the doses were administered approximately 4 weeks apart.
HI antibody geometric mean titers (GMTs) and seroconversion rates 28 days following vaccination with FluQuadri were non-inferior to those following each TIV for all four strains, based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio of GMTs [FluQuadri divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain] was >0.66 and the lower limit of the 2-sided 95% CI of the difference in seroconversion rates [FluQuadri minus pooled TIV for the A strains, or the TIV containing the corresponding B strain] was >-10%). For strain A/H1N1, the GMT ratio was 1.03 (95% CI: 0.93; 1.14) and the difference of seroconversion rates was 0.9% (95% CI: -0.9%; 3.0%). For strain A/H3N2, the GMT ratio was 0.99 (95% CI: 0.91; 1.08) and the difference of seroconversion rates was 3.8% (95% CI: 1.4%; 6.3%). For strain B/Brisbane/60/2008 (B Victoria), the GMT ratio was 1.34 (95% CI: 1.20; 1.50) and the difference of seroconversion rates was 10.7% (95% CI: 6.4%; 15.1%). For strain B/Florida/04/2006 (B Yamagata), the GMT ratio was 1.06 (95% CI: 0.94; 1.18) and the difference of seroconversion rates was 2.0% (95% CI: -2.2%; 6.4%). Non-inferiority immunogenicity criteria based on HI antibody GMTs and seroconversion rates were also met when age subgroups (6 months to <36 months and 3 years to <9 years) were examined.
In addition, HI antibody GMTs and seroconversion rates following FluQuadri were higher than those following TIV for the B strain not contained in each respective TIV based on prespecified criteria (the lower limit of the 2-sided 95% CI of the ratio of the GMTs [FluQuadri divided by TIV] >1.5 for each B strain in FluQuadri compared with the corresponding B strain not contained in each TIV and the lower limit of the two 2-sided 95% CI of the difference of the seroconversion rates [FluQuadri minus TIV] >10% for each B strain in FluQuadri compared with the corresponding B strain not contained in each TIV).
Immunogenicity of a 0.5 mL Dose of FluQuadri in Children 6 Months through 35 Months of Age: In Study 2 (NCT02915302) [see ADVERSE REACTIONS], 1027 children, 6 months through 35 months of age, were included in the per-protocol immunogenicity analysis. The distribution of demographic characteristics was similar to that of the safety analysis set [see ADVERSE REACTIONS].
GMT ratios (GMT_{0.5-mL dose} divided by GMT_{0.25-mL dose}) for the A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage strains were 1.42 (95% CI: 1.16; 1.74), 1.48 (95% CI: 1.21; 1.82), 1.33 (95% CI: 1.09; 1.62), and 1.41 (95% CI: 1.17; 1.70), respectively. Seroconversion rate (SCR) differences (SCR_{0.5-mL dose} minus SCR_{0.25-mL dose}) for the A/H1N1, A/H3N2, B Victoria lineage, and B Yamagata lineage strains were 4.6% (95% CI: -0.4%; 9.6%), 5.1% (95% CI: 0.4%; 9.8%), 1.3% (95% CI: -2.9%; 5.6%), and 2.6% (95% CI: -1.4%; 6.5%). HI antibody GMTs and seroconversion rates 28 days following final vaccination with a 0.5-mL dose of FluQuadri were non-inferior to those following a 0.25-mL dose for all four strains, based on pre-specified criteria (lower limit of the 2-sided 95% CI of the ratio of GMTs between groups > 0.667; lower limit of the 2-sided 95% CI of the difference in seroconversion rates > -10%).
Immunogenicity of FluQuadri in Adults ≥18 years of Age: In a multi-center study conducted in the US, 565 adults 18 years of age and older who had received one dose of FluQuadri, TIV-1, or TIV-2 were included in the per-protocol immunogenicity analysis.
HI antibody GMTs 21 days following vaccination with FluQuadri were non-inferior to those following each TIV for all four strains, based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio of GMTs [FluQuadri divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain] was >²/₃). For strain A/H1N1, the GMT ratio was 1.06 (95% CI: 0.87; 1.31), for strain A/H3N2, the GMT ratio was 0.90 (95% CI: 0.70; 1.15), for strain B/Brisbane/60/2008 (B Victoria), the GMT ratio was 0.89 (95% CI: 0.70; 1.12) and for strain B/Florida/04/2006 (B Yamagata), the GMT ratio was 1.15 (95% CI: 0.93; 1.42).
Immunogenicity of FluQuadri in Geriatric Adults ≥65 years of Age: In a multi-center study conducted in the US, 660 adults 65 years of age and older were included in the per-protocol immunogenicity analysis.
HI antibody GMTs 21 days following vaccination with FluQuadri were non-inferior to those following TIV for all four strains, based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio of GMTs [FluQuadri divided by pooled TIV for the A strains, or the TIV containing the corresponding B strain] was >0.66). For strain A/H1N1, the GMT ratio was 0.85 (95% CI: 0.67; 1.09), for strain A/H3N2, the GMT ratio was 1.55 (95% CI: 1.25; 1.92), for strain B/Brisbane/60/2008 (B Victoria), the GMT ratio was 1.27 (95% CI: 1.05; 1.55) and for strain B/Florida/04/2006 (B Yamagata), the GMT ratio was 1.11 (95% CI: 0.90; 1.37). Seroconversion rates 21 days following FluQuadri were non-inferior to those following TIV for H3N2, B/Brisbane, and B/Florida, but not for H1N1, based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the difference in seroconversion rates [FluQuadri minus pooled TIV for the A strains, or the TIV containing the corresponding B strain] was >-10%). For strain A/H1N1, the difference of seroconversion rates was -3.86% (95% CI: -11.50%; 3.56%), for strain A/H3N2, the difference of seroconversion rates was 9.77% (95% CI: 1.96%; 17.20%), for strain B/Brisbane/60/2008 (B Victoria), the difference of seroconversion rates was 9.91% (95% CI: 1.96%; 17.70%), and for strain B/Florida/04/2006 (B Yamagata), the difference of seroconversion rates was 1.96% (95% CI: -6.73%; 10.60%).
The HI antibody GMT following FluQuadri was higher than that following TIV-1 for B/Florida but not higher than that following TIV-2 for B/Brisbane, based on pre-specified criteria (the lower limit of the 2-sided 95% CI of the ratio of the GMTs [FluQuadri divided by TIV] >1.5 for each B strain in FluQuadri compared with the corresponding B strain not contained in each TIV). The GMT ratio for B/Brisbane was 1.75 (95% CI: 1.43; 2.14). Seroconversion rates following FluQuadri were higher than those following TIV for the B strain not contained in each respective TIV, based on prespecified criteria (the lower limit of the two 2-sided 95% CI of the difference of the seroconversion rates [FluQuadri minus TIV] >10% for each B strain in FluQuadri compared with the corresponding B strain not contained in each TIV).
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: FluQuadri has not been evaluated for carcinogenic or mutagenic potential or for impairment of fertility.