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Flucelvax

"The U.S. Food and Drug Administration today approved the first adjuvanted vaccine for the prevention of H5N1 influenza, commonly known as avian or bird flu. The vaccine, Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted, is for use in peopl"...

Flucelvax

CLINICAL PHARMACOLOGY

Mechanism Of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance and analysis of influenza virus isolates permits identification of yearly antigenic variants. Since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers induced by vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza illness. In some studies, HI antibody titers of ≥ 1:40 have been associated with protection from influenza illness in up to 50% of subjects.2,3

Antibody against one influenza virus type or subtype confers little or no protection against another. Furthermore, antibody 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 strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinin of influenza virus strains representing the influenza viruses likely to circulate in the United States in the upcoming winter.

Annual influenza vaccination is recommended by the Advisory Committee on Immunization Practices because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.4

Clinical Studies

Efficacy Against Culture-Confirmed Influenza

A multinational (US, Finland, and Poland), randomized, observer-blind, placebo-controlled trial (study 1) was performed to assess clinical efficacy and safety of FLUCELVAX during the 2007-2008 influenza season in adults aged 18 through 49 years. A total of 11,404 subjects were enrolled to receive FLUCELVAX (N=3828), AGRIFLU (N=3676) or placebo (N=3900) in a 1:1:1 ratio. Among the overall study population enrolled, the mean age was 33 years, 55% were female, 84% were Caucasian, 7% were Black, 7% were Hispanic, and 2% were of other ethnic origin.

FLUCELVAX efficacy was assessed by the prevention of culture-confirmed symptomatic influenza illness caused by viruses antigenically matched to those in the vaccine and prevention of influenza illness caused by all influenza viruses compared to placebo. Influenza cases were identified by active and passive surveillance of influenza-like illness (ILI). ILI was defined as a fever (oral temperature ≥ 100.0°F / 38°C) and cough or sore throat. Nose and throat swab samples were collected for analysis within 120 hours of onset of an influenza-like illness in the period from 21 days to 6 months after vaccination. Overall vaccine efficacy against all influenza viral subtypes and vaccine efficacy against individual influenza viral subtypes were calculated (Tables 3 and 4, respectively).

Table 3: Vaccine Efficacy against Culture-Confirmed Influenza (Study 1)

  Number of subjects per protocol Number of subjects with influenza Attack Rate (%) Vaccine Efficacy1,2
% Lower Limit of OneSided 97.5% CI of VE2, 3
Antigenically Matched Strains
  FLUCELVAX 3776 7 0.19 83.8 61.0
  Placebo 3843 44 1.14 -- --
All Culture-Confirmed Influenza
  FLUCELVAX 3776 42 1.11 69.5 55.0
  Placebo 3843 140 3.64 -- --
1Efficacy against influenza was evaluated over a 9 month period in 2007/2008
2Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 - Relative Risk) x 100 %
3VE success criterion: the lower limit of the one-sided 97.5% CI for the estimate of the VE relative to placebo is > 40%

Table 4: Efficacy of FLUCELVAX against Culture-Confirmed Influenza by Influenza Viral Subtype (Study 1)

  FLUCELVAX
(N=3776)
Placebo
(N=3843)
Vaccine Efficacy2
Attack Rate (%) Number of Subjects with Influenza Attack Rate (%) Number of Subjects with Influenza % Lower Limit of One-Sided 97.5% CI of VE1,2
Antigenically Matched Strains
A/H3N23 0. 05 2 0 0 -- --
A/H1N1 0.13 5 1.12 43 88.2 67.4
B3 0 0 0.03 1 -- --
All Culture-Confirmed Influenza
A/H3N2 0.16 6 0.65 25 75.6 35.1
A/H1N1 0.16 6 1.48 57 89.3 73.0
B 0.79 30 1.59 61 49.9 18.2
1No VE success criterion was prespecified in the protocol for each individual influenza virus subtype.
2 Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of FLUCELVAX relative to placebo based on the Sidak-corrected score confidence intervals for the relative risk. Vaccine Efficacy = (1 - Relative Risk) x 100 %;
3 There were too few cases of influenza due to vaccine-matched influenza A/H3N2 or B to adequately assess vaccine efficacy.

Immunogenicity In Adults 18 through 64 Years Of Age

Immunogenicity data in adults 18 through 64 years of age were derived from 3 clinical studies, including 1353 subjects that received FLUCELVAX. Immune responses measured by hemagglutination inhibition (HI) antibody titers to each virus strain in the vaccine were evaluated in sera obtained 21 days after administration of FLUCELVAX or comparator vaccine.

These studies included clinical study 1 performed in 2007-2008 in the US, Finland and Poland, in which immunogenicity was evaluated in a subset of 978 subjects enrolled at US sites (228, 695, and 55 for FLUCELVAX, AGRIFLU, and placebo, respectively). Among the overall study population enrolled, 58% were female; 67% were Caucasian, 20% Hispanic, 11% Black, 1% Asian and 1% of other ethnic origin; and the mean age was 33 years.

In clinical study 2 conducted in Poland in 2004-2005, immunogenicity data were obtained for 1655 subjects (818 and 837 for FLUCELVAX and AGRIFLU, respectively). Among the overall study population enrolled, 59% were female, 100% of subjects were Caucasian, and the mean age was 43.6 years.

In clinical study 3 conducted in the US in 2005-2006, immunogenicity data were obtained for 610 subjects (307 and 303 for FLUCELVAX and FLUVIRIN, respectively). Among the overall study population enrolled, 64% were female, 96% were Caucasian, and the mean age was 33.9 years. Immunogenicity results are shown separately for the age cohorts 18 through 49 years of age (for which clinical endpoint efficacy data are available, Table 3 and Table 4) and 50 through 64 years of age in Tables 5 and 6.

For all studies outlined in Table 5, antibody responses after vaccination were evaluated according to percentages of subjects with HI antibody titers ≥ 1:40 and seroconversion. For subjects 18 through 64 years of age, success was defined as 1) the lower bound of the two-sided 95% CI for the percent of subjects achieving an HI antibody titer ≥ 1:40 should meet or exceed 70% and 2) the lower bound of the two-sided 95% CI for the percent of subjects achieving seroconversion for HI antibody should meet or exceed 40% (Table 5).

Table 5: Percentage (%) of subjects with Post-Vaccination HI Titers ≥ 1:40 and Seroconversion in Adult FLUCELVAX Recipients 18 through 49 Years and 50 through 64 Years of Age

Study Vaccine strain 18 through 49 Years 50 through 64 Years
% HI Titer ≥ 1:40 (95% CI)
N=228
% Seroconversion1 (95% CI)
N=228
% HI Titer ≥ 1:40 (95% CI) % Seroconversion1 (95% CI)
Study 1 US, Finland, Poland 2007- 2008 N=228 A/H1N1 99 (97-100) 78 (72-83)    
A/H3N2 99 (98-100) 59 (53-66)    
B 78 (72-83) 51 (45-58)    
    N=478 N=478 N=340 N=340
Study 2 Poland 2004- A/H1N1 94 (91-96) 73 (69-77) 84 (79-88) 57 (52-63)
    18 through 49 Years 50 through 64 Years
2005 N=818 A/H3N2 99 (98-100) 63 (59-68) 99 (97-100) 66 (61-71)
B 93 (90-95) 88 (84-90) 87 (83-90) 77 (70-79)
    N=307 N=307    
Study 3 US 2005- 2006 N=307 A/H1N1 96 (94-98) 62 (57-68)    
A/H3N2 91 (87-94) 85 (81-89)    
B 94 (91-96) 77 (72-81)    
1 Rates of seroconversion = percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer ≥ 1:40 or a pre-vaccination HI titer ≥ 1:10 and at least a four-fold rise in post-vaccination HI antibody titer

Non-inferiority in Adults 18 through 64 Years of Age

In study 2, non-inferiority of FLUCELVAX to AGRIFLU was demonstrated for HI antibody responses to all three strains for both post-vaccination geometric mean titer (GMT) ratios and seroconversion rates. Success for non-inferiority of the GMT ratio was defined as the lower limit of the two-sided 95% CI for GMT ratio (FLUCELVAX / AGRIFLU) was > 0.67; and success for non-inferiority of seroconversion rate was defined as the lower limit of the two-sided 95% CI for the difference between the seroconversion rates (FLUCELVAX – AGRIFLU) was > -10%) (Table 6).

Table 6: Non-inferiority Analysis of FLUCELVAX to a US licensed Comparator in Adults 18 through 49 Years and 50 through 64 Years of Age (Study 2)

  Vaccine Group Ratio/Difference (95% CI) FLUCELVAX Versus Comparator1
A/H1N1 A/H3N2 B
Subjects 18 through 49 Years: N Flucevax=478; N comparator=472
GMTs ratio (Flucelvax / Agriflu) 0.96 (0.81, 1.13) 0.98 (0.87, 1.11) 1.07 (0.93, 1.23)
Difference in Seroconversion Rates2 (Flucelvax - Agriflu) 2% (-4, 8) 2% (-5, 8) 5% (1, 10)
Subjects 50 through 64 Years: N Flucevax=340; N comparator=365
GMTs ratio (Flucelvax / Agriflu) 0.96 (0.79, 1.16) 0.87 (0.74, 1.02) 1.23 (1.02, 1.48)
Difference in Seroconversion Rates (Flucelvax - Agriflu) 1% (-6, 8) -2% (-9, 5) 3% (-4, 9)
1 AGRIFLU
2Rates of seroconversion = percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer ≥ 1:40 or a pre-vaccination HI titer ≥ 1:10 and at least a four-fold rise in post-vaccination HI antibody titer

Immunogenicity In Adults 65 Years Of Age And Older

In clinical study 2, a post-hoc analysis of immune response to Flucelvax among adults 65 years of age and older was performed. In this study, 985 subjects 65 years of age or older (504 and 481 for FLUCELVAX and AGRIFLU, respectively) were evaluated. Of these subjects, 56% were female, 100% were Causacian, and the mean age was 71.3 years.

Antibody responses to Flucelvax in this older population were evaluated according to percentages of subjects with seroconversion and HI Titer ≥ 1:40 (Table 7) and were compared to antibody responses for non-inferiority to a licensed comparator vaccine (Agriflu, Table 8).

For subjects 65 years of age and older, success was defined as 1) the lower bound of the two-sided 95% CI for the percent of subjects achieving HI an antibody titer ≥ 1:40 should meet or exceed 60% and 2) the lower bound of the two-sided 95% CI for the percent of subjects achieving seroconversion for HI antibody should meet or exceed 30%.

Table 7: Percentage (%) of subjects with Post-Vaccination HI Titers ≥ 1:40, Seroconversion Rate in Adult FLUCELVAX Recipients 65 Years of Age and Older (Study 2)

  Vaccine strain % of Subjects with HI Titer ≥ 1:40 (95% CI) % of Subjects with Seroconversion1 (95% CI)
Study 2 Poland 2004-2005 N=504 A/H1N1 86(83-89) 55(50-59)
A/H3N2 97(95-98) 68(64-72)
B 90(87-93) 80(76-84)
1Rates of seroconversion = percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer ≥ 1:40 or a pre-vaccination HI titer ≥ 1:10 and at least a four-fold rise in post-vaccination HI antibody titer.

Non-inferiority in Adults 65 Years of Age and Older

Non-inferiority of FLUCELVAX to AGRIFLU was demonstrated for HI antibody responses to all three strains for both post-vaccination GMT ratios and seroconversion rates. Success for non-inferiority of the GMT ratio was defined as the lower limit of the two-sided 95% CI for the GMT ratio (FLUCELVAX / AGRIFLU) > 0.67; and success for non-inferiority of seroconversion rate was defined as the lower limit of the two-sided 95% CI for the difference between the seroconversion rates (FLUCELVAX – AGRIFLU) > -10%) (Table 8).

Table 8: Non-inferiority Analysis of FLUCELVAX to a US licensed Comparator in Adults 65 Years of Age and Older (Study 2)

  Vaccine Group Ratio/Difference (95% CI) FLUCELVAX Versus Comparator1 (N FLUCELVAX=504; N comparator=481)
A/H1N1 A/H3N2 B
GMTs ratio (FLUCELVAX / Agriflu) 1.06 (0.92, 1.22) 0.97 (0.84, 1.12) 1.28 (1.1, 1.48)
Difference in Seroconversion Rates2 (FLUCELVAX -Agriflu) -1% (-7, 6) 3% (-2, 9) 7% (1, 12)
1AGRIFLU
2Rates of seroconversion = percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer ≥ 1:40 or a pre-vaccination HI titer ≥ 1:10 and at least a four-fold rise in post-vaccination HI antibody titer.

REFERENCES

1. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998; 339(25):1797-1802.

2. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138.

3. Hobson D, Curry RL, Beare A, et.al. The role of serum hemagglutinin-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972; 767-777.

4. Centers for Disease Control and Prevention. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011; 60(33): 1128-1132.

Last reviewed on RxList: 9/11/2014
This monograph has been modified to include the generic and brand name in many instances.

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