Flublok Trivalent Mechanism of Action

Pharmacotherapeutic group: Influenza vaccine. ATC code: J07BB02.
Pharmacology: Pharmacodynamics: Immunogenicity studies performed with quadrivalent recombinant influenza vaccine (Flublok Quadrivalent): Flublok Quadrivalent was evaluated in healthy adults of 18-49 years of age in a randomised, observer-blind, active controlled, non-inferiority immunogenicity, multi-center trial conducted during the 2014-2015 influenza season in the United States (study 1).
In the study 1, subjects received Flublok Quadrivalent (N=998) or an egg-based quadrivalent inactivated influenza vaccine (IIV4) (N=332). Immunogenicity was assessed before and 28 days after administration of a single dose of study vaccine.
Haemagglutination inhibition (HAI) geometric mean titers (GMTs) were determined for the two vaccine groups for each vaccine antigen.
Immunogenicity was compared by calculating the difference in seroconversion rates (SCR) and the ratios of GMTs of Comparator to Flublok Quadrivalent.
Study 1 had two co-primary endpoints: GMTs and Day 28 HAI seroconversion rates for each of the four antigens contained in the study vaccines.
Flublok Quadrivalent met the success criterion for GMTs for three of the four antigens but did not meet the success criteria for the B/Victoria lineage antigen (see Table 1).
Antibody titres against the B/Victoria were low in both vaccine groups.

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Flublok Quadrivalent met the success criterion for SCRs for three of the four antigens (see Table 2), but not for the B/Victoria lineage. The HAI response to the B/Victoria lineage antigen was low in both vaccine groups.

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The study 1 in adults 18-49 years of age was conducted in parallel to the study 2 in adults of 50 years of age and older. These adults 18-49 years of age were vaccinated during the same influenza season (2014-2015 Northern Hemisphere influenza season) and received the same Flublok Quadrivalent formulation (same vaccine strain composition) as adults of 50 years of age and older in the study 2. The immune response induced by Flublok Quadrivalent was assessed by the same HAI assay and performed by the same laboratory for both studies. The immunogenicity results in adults 18-49 years of age (study 1) and adults 50 years of age and older (study 2) are presented in Table 3. (See Table 3.)

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These immunogenicity data provide supportive information for the 18-49 years of age group in addition to vaccine efficacy data available in adults ≥50 years of age (see Clinical Efficacy).
Clinical efficacy of Flublok Quadrivalent (quadrivalent recombinant influenza vaccine): The efficacy of Flublok Quadrivalent (quadrivalent recombinant influenza vaccine) is relevant to Flublok Trivalent because both vaccines are manufactured using the same process and have overlapping compositions.
Flublok Quadrivalent efficacy in terms of prevention of laboratory-confirmed influenza-like illness (ILI) caused by any strain of influenza, was evaluated in adults ≥50 years of age and conducted during the 2014-2015 influenza season in the United States (study 2). A total of 8,963 healthy, medically stable adults were randomised in a 1:1 ratio to receive a single dose of Flublok Quadrivalent (n=4,474) or an egg-based quadrivalent inactivated influenza vaccine (n=4,489).
A total of 5,412 (60.4%) subjects were 50-64 years of age, 2,532 (28.2%) were 65-74 years of age and 1,019 (11.4%) were ≥75 years of age.
The primary efficacy endpoint of Study 2 was reverse transcriptase polymerase chain reaction (rtPCR)-positive, protocol-defined ILI due to any strain of influenza.
Laboratory-confirmed protocol defined ILI was defined as having at least one symptom in each of two categories of respiratory and systemic symptoms, which could include sore throat, cough, sputum production, wheezing and difficulty breathing, or systemic symptoms such as fever >99°F (>37°C) , chills, fatigue, headache and myalgia, laboratory-confirmed by rtPCR.
US epidemiological data for the 2014-2015 influenza season indicated that Influenza A (H3N2) viruses predominated and that most influenza A/H3N2 viruses were antigenically dissimilar while A/H1N1 and B viruses were antigenically similar to vaccine antigens. Flublok Quadrivalent met the pre-specified success criterion for non-inferiority to the comparator pre-defined as a lower bound of the two sided 95% CI >-20%.
Of the 4,474 participants exposed to Flublok Quadrivalent in a phase 3 active-controlled study (Study 2), a total of 1,761 were 65 years or older. Although no differences in safety or efficacy were observed between older and younger participants, the number of patients aged 65 and over in this study was not sufficient to determine statistically whether this age group will respond differently from younger individuals. (See Table 4.)

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Clinical efficacy of Flublok Trivalent (trivalent recombinant influenza vaccine): The efficacy of Flublok Trivalent in protecting against influenza illness was evaluated in a randomised, observer-blind, placebo-controlled multicenter trial conducted in the United States during the 2007-2008 influenza season in adults 18-49 years of age (Study 3). Study 3 enrolled and vaccinated 4,648 healthy adults randomised in a 1:1 ratio to receive a single dose of Flublok Trivalent (n=2,344) or saline placebo (n=2,304).
The primary efficacy endpoint of Study 3 was defined as an influenza-like illness (ILI) with a positive culture for an influenza virus strain antigenically resembling a strain represented in Flublok Trivalent. ILI is defined as fever of ≥100°F (37.8°C) oral accompanied by cough, sore throat, or both, on the same or consecutive days. Attack rates and vaccine efficacy (VE), defined as the reduction in the influenza rate for RIV3 relative to placebo, were calculated for the total vaccinated cohort (n=4,648).
Due to very small number of cultured confirmed influenza cases with matched strains, an exploratory analysis of VE of Flublok Trivalent against all strains, regardless of antigenic match, isolated from any subject with an ILI, not necessarily meeting ILI criteria was done, demonstrated an efficacy estimate of 44.8% (95% CI 24.4, 60.0). See Table 5 for VE by case definition. (See Table 5.)

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Paediatric population: The licensing authority has waived the obligation to submit the results of studies with Flublok Trivalent in children under 9 years of age for the prevention of influenza infection.
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non-clinical safety data on Flublok Trivalent revealed no special hazard for humans based on conventional studies of repeat dose and local toxicity, reproductive and developmental (including teratogenicity) toxicity and safety pharmacology studies.