April 23, 2017
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Flublok

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Flublok

CLINICAL PHARMACOLOGY

Mechanism Of Action

Flublok contains recombinant HA proteins of the three strains of influenza virus specified by health authorities for inclusion in the annual seasonal vaccine. These proteins function as antigens which induce a humoral immune response, measured by hemagglutination inhibition (HI) antibody).

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 replacement of one or more influenza virus strains in each year's influenza vaccine. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains (i.e., typically two type A and one type B), representing the influenza viruses likely to be circulating in the U.S. in the upcoming winter.

Clinical Studies

Efficacy Against Laboratory-Confirmed Influenza

The efficacy of Flublok (trivalent formulation) in protecting against culture-confirmed influenza illness was evaluated in a randomized, observer-blind, placebo-controlled multicenter trial conducted in the U.S. during the 2007-2008 influenza season in adults 18-49 years of age (Study 1). (1)

Study 1 enrolled and vaccinated 4648 healthy adults (mean age 32.5 years) randomized in a 1:1 ratio to receive a single dose of Flublok (n=2344) or saline placebo (n=2304). Among enrolled subjects, 59% were female, 67% were white, 19% African-American, 2% Asian, < 1% other races, and 11% of Latino/Hispanic ethnicity. Culture-confirmed influenza was assessed by active and passive surveillance for influenza-like illness (ILI) beginning 2 weeks post-vaccination until the end of the influenza season, approximately 7 months post- vaccination. ILI was defined as having at least 2 of 3 symptoms (no specified duration) in the following categories: 1) fever ≥ 100°F; 2) respiratory symptoms (cough, sore throat, or runny nose/stuffy nose); or 3) systemic symptoms (myalgias, arthralgias, headache, chills/sweats, or tiredness/malaise). For subjects with an episode of ILI, nasal and throat swab samples were collected for viral culture.

The primary efficacy endpoint of Study 1 was Centers for Disease Control-defined influenza-like illness (CDC-ILI) with a positive culture for an influenza virus strain antigenically resembling a strain represented in Flublok. CDC-ILI is defined as fever of ≥ 100°F oral accompanied by cough, sore throat, or both on the same day or on consecutive days. Attack rates and vaccine efficacy (VE), defined as the reduction in the influenza rate for Flublok relative to placebo, were calculated for the total vaccinated cohort (n=4648).

The pre-defined success criterion for the primary efficacy analysis was that the lower bound of the 95% confidence interval (CI) of VE should be at least 40%. Vaccine efficacy against antigenically matched culture-confirmed CDC-ILI could not be determined reliably because 96% of the influenza isolates obtained from subjects in Study 1 were not antigenically matched to the strains represented in the vaccine. An exploratory analysis of VE of Flublok against all strains, regardless of antigenic match, isolated from any subject with an ILI, not necessarily meeting CDC- ILI criteria, demonstrated an efficacy estimate of 44.8% (95% CI 24.4, 60.0). See Table 4 for a presentation of VE by case definition and antigenic similarity. Protein Sciences Corporation Influenza Vaccine Package Insert BLA STN 125285 Flublok PI (V4.3), 2016 Page 13 of 16

Table 4: Vaccine Efficacy Against Culture-Confirmed Influenza in Healthy Adults 18-49 Years of Age, Study 1*

Case definition Flublok
(N=2344)
Saline Placebo
(N=2304)
Flublok Vaccine Efficacy1, % 95% Confidence Interval
Cases, n Rate, % Cases, n Rate, %
Positive culture with a strain represented in the vaccine
CDC-ILI, all matched strains2,3 1 0.04 4 0.2 75.4 (-148.0, 99.5)
Any ILI, all matched strains4,5 2 0.1 6 0.3 67.2 (-83.2, 96.8)
Positive culture with any strain, regardless of match to the vaccine
CDC-ILI, all strains2,6 44 1.9 78 3.4 44.6 (18.8, 62.6)
  Sub-Type A 26 1.1 56 2.4 54.4 (26.1, 72.5)
  Type B 18 0.8 23 1.0 23.1 (-49.0, 60.9)
Any ILI, all strains4 64 2.7 114 4.9 44.8 (24.4, 60.0)
  Sub-Type A 41 1.7 79 3.4 49.0 (24.7, 65.9)
  Type B 23 1.0 36 1.6 37.2 (-8.9, 64.5)

*In Study 1 (NCT00539981) vaccine efficacy analyses were conducted on the Total Vaccinated Cohort (all randomized subjects who received study vaccine according to the treatment actually received and who provided data). Vaccine efficacy (VE) = 1 minus the ratio of Flublok/placebo infection rates.
1 Determined under the assumption of Poisson event rates, according to Breslow and Day, 1987.
2 Meets CDC influenza-like illness (CDC-ILI) defined as fever of ≥ 100°F oral accompanied by cough and/or sore throat, on the same day or on consecutive days.
3 Primary endpoint of trial.
4 All culture-confirmed cases are considered, regardless of whether they qualified as CDC-ILI.
5 Secondary endpoint of trial.
6 Exploratory (prespecified) endpoint of trial.

The efficacy of Flublok Quadrivalent is relevant to Flublok (trivalent formulation) because both vaccines are manufactured using the same process and have overlapping compositions (see DESCRIPTION).

Study 6 evaluated the efficacy of Flublok Quadrivalent in a randomized, observer-blind, active-controlled, multi-center trial conducted during the 2014-2015 influenza season in adults 50 years of age and older. A total of 8963 healthy, medically stable adults (mean age 62.5 years) were randomized in a 1:1 ratio to receive a single dose of Flublok Quadrivalent (n=4474) or a U.S.-licensed quadrivalent inactivated influenza vaccine (Comparator, Fluarix Quadrivalent, manufactured by Glaxo SmithKline) (n=4489). Among randomized subjects, 58% were female, 80% white, 18% black/African-American, 2% other races, and 5% of Hispanic/Latino ethnicity. A total of 5186 (60%) subjects were 50-64 years of age and 3486 (40%) were ≥ 65 years of age. Real-time polymerase chain reaction (rtPCR) -confirmed influenza was assessed by active and passive surveillance for influenza-like illness (ILI) beginning 2 weeks post-vaccination until the end of the influenza season, approximately 6 months post- vaccination. ILI was defined as having at least one symptom (no specified duration) in each of two categories of respiratory and systemic symptoms. Respiratory symptoms included sore throat, cough, sputum production, wheezing and difficulty breathing. Systemic symptoms included fever > 99°F ( > 37°C) oral, chills, fatigue, headache and myalgia. For subjects with an episode of ILI, a nasopharyngeal swab sample was collected for rtPCR testing and reflex viral culture of rtPCR-positive samples.

The primary efficacy endpoint of Study 6 was rtPCR-positive, protocol-defined ILI due to any strain of influenza. Attack rates and relative vaccine efficacy (rVE), defined as 1 - [Attack rate Flublok Quadrivalent/ Attack Rate Comparator], were calculated for the total efficacy population (n=8604) for the primary efficacy endpoint and for several alternative efficacy endpoints (Table 5). Antigenic and phylogenetic evaluations of the similarity (“matching”) of clinical isolates to vaccine antigens were not performed. CDC 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.

Table 5: Relative Vaccine Efficacy (rVE) of Flublok Quadrivalent versus Comparator against Laboratory-Confirmed Influenza, Regardless of Antigenic Similarity to Vaccine Antigens, Adults 50 Years of Age and Older, Study 6 (Efficacy Population)1,2

  Flublok Quadrivalent
(N=4303)
Comparator
(N=4301)
RR rVE % (95% CI)
n Attack Rate % (n/N) n Attack Rate % (n/N)
All rtPCR-positive Influenza3 96 2.2 138 3.2 0.70 30
(10, 47)
All rtPCR-positive Influenza A4 73 1.7 114 2.7 0.64 36
(14,53)
All rtPCR-positive Influenza B4 23 0.5 24 0.6 0.96 4
(-72, 46)
All Culture-confirmed Protocol-defined ILI4,5 58 1.3 101 2.3 0.57 43
(21, 59)
Abbreviations: rtPCR=reverse transcriptase polymerase chain reaction; Comparator=U.S.-licensed quadrivalent inactivated influenza vaccine, Fluarix Quadrivalent, manufactured by GlaxoSmithKline; n=number of influenza cases; N=number of subjects in treatment group; RR=relative risk (Attack Rate Flublok/Attack Rate IIV4); rVE = [(1-RR) x 100].
1Study 2 is registered as NCT02285998.
2Efficacy Population included all randomized subjects who received study vaccine and provided any follow-up documentation for influenza-like illness beginning at least 14 days post-vaccination. Excluded subjects with protocol deviations that could adversely affect efficacy.
3Primary Analysis. All cases of rtPCR-confirmed influenza are included. Antigenic characterization and genetic sequencing to determine similarity of isolates to vaccine antigens were not performed. CDC surveillance data indicated that the majority of influenza A/H3N2 wild type viruses were antigenically distinct whereas influenza A/H1N1 and type B viruses were antigenically similar to vaccine antigens during the 2014-2015 season. Study 2 met the pre-specified success criterion for the primary endpoint (lower limit of the 2-sided 95% CI of vaccine efficacy for Flublok Quadrivalent relative to Comparator should be not less than -20%).
4 Post hoc analyses. All cases of influenza A were A/H3N2. Cases of influenza B were not distinguished by lineage.
5 Culture of rtPCR-positive samples was performed in MDCK cells.

REFERENCES

1. Treanor JJ, El Sahly HM, King J, et. al. Protective efficacy of a trivalent recombinant hemagglutinin protein vaccine (FluBlok) against influenza in healthy adults: a randomized, placebo-controlled trial. Vaccine. 2011, Vol. 29, pp. 7733-7739.

4. Izikson R, Leffell DJ, Bock SA, et. al. Randomized comparison of the safety of Flublok®versus licensedinactivated influenza vaccine in healthy, medically stable adults ≥ 50years of age. Vaccine. 2015, Vol. 33 , pp. 6622-6628.

5. Treanor JJ, Schiff GM, Hayden FG, et.al. Safety and immunogenicity of a baculovirus-expressed hemagglutinin influenza vaccine: a randomized controlled trial. JAMA. 2007, Vol. 297, pp. 1577-1582.

6. King JC, Cox MMJ, Reisinger K, et. al. Evaluation of the safety, reactogenicity and immunogenicity of FluBlok tirvalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy children aged 6-59 months. Vaccine. 2009, Vol. 27, pp. 6589-6594.

7. CBER/FDA. Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines. s.l. : DHHS/CBER/FDA, 2007.

Last reviewed on RxList: 10/20/2016
This monograph has been modified to include the generic and brand name in many instances.

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