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Flucelvax

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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.4,5

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.6

Clinical Studies

Efficacy against Culture-Confirmed Influenza

A multinational (US, Finland, and Poland), randomized, observer-blinded, 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. Efficacy against individual influenza viral subtypes was calculated (Tables 3 and 4).

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

  Number of subjects per protocol Number of subjects with influenza Attack Rate (%) Vaccine Efficacy**
% Lower Limit of One Sided 97.5% CI of VE
Antiqenicallv 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 -- --
* NCT00630331
** Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of each influenza vaccine relative to placebo based on the Sidak-corrected score confidence intervals for the two relative risks. Vaccine Efficacy = (1 – Relative Risk) x 100 %

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

  FLUCELVAX (N=3776) Placebo (N=3843) Vaccine Efficacy**
Attack Rate (%) Number of Subjects with Influenza Attack Rate (%) Number of Subjects with Influenza % Lower Limit of One-Sided 97.5% CI of VE
  Antigenically Matched Strains
A/H3N2*** 0. 05 2 0 0
A/H1N1 0.13 5 1.12 43 88.2 67.4
B*** 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
* NCT00630331
** Simultaneous one-sided 97.5% confidence intervals for the vaccine efficacy (VE) of each influenza vaccine relative to placebo based on the Sidak-corrected score confidence intervals for the two relative risks. Vaccine Efficacy = (1 - Relative Risk) x 100 %;
*** 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

Data evaluating immunogenicity 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.

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. 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, the following immunogenicity endpoints were assessed: 1) the lower bound of the two-sided 95% confidence intervals (CI) for the percentage of subjects with HI antibody titers ≥ 1:40 after vaccination, and 2) the lower bounds of the two-sided 95% CIs for percentages of subjects with seroconversion (defined as 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) (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 %) % Seroconversion **** (95% CI %) % HI Titer ≥ 1:40 (95% CI %) % Seroconversion **** (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)    
Study 2** Poland 2004-2005 N=818 A/H1N1 94 (91-96) 73 (69-77) 84 (79-88) 57 (52-63)
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)
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)    
* NCT00630331,
** NCT00492063,
*** NCT002645767;
**** Rates of seroconversion = percentage of subjects with either a pre-vaccination HI titer < 1:10 and a postvaccination 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 (i.e. the lower limit of the twosided 95% CI for the ratio of the GMTs (FLUCELVAX / AGRIFLU) was > 0.67; and the lower limit of the two-sided 95% CI for the difference between the seroconversion rates (FLUCELVAX and 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 Comparator**
A/H1N1 A/H3N2 B
Subjects 18 through 49 years
GMTs ratio(FLUCELVAX / Agriflu) 0.96 (0.81, 1.13) 0.98 (0.87, 1.11) 1.07 (0,93, 1,23)
Difference in Serocon-version Rates*** (FLUCELVAX - Agriflu) 2% (-4, 8) 2% (-5, 8) 5% (1, 10)
Subjects 50 through 64 Years
GMTs ratio(FLUCELVAX / Agriflu) 0.96 0.87 1.23
(0.79, 1.16) (0.74, 1.02) (1,02, 1,48)
Difference in Serocon-version Rates*** (FLUCELVAX - Agriflu) 1% (-6, 8) -2% (-9, 5) 3% (-4, 9)
* NCT00492063
** AGRIFLU
*** Rates of seroconversion = percentage of subjects with either a pre-vaccination HI titer < 1:10 and a postvaccination 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, an analysis of adults 65 years of age and older was performed by a post-hoc re-stratification of the age ranges. 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 (Table 7).

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 Seroconversion** (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)
*NCT00492063
**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 65 Years of Age and Older

In adults 65 years of age or older enrolled in study 2, 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 (i.e. the lower limit of the two-sided 95% CI for the ratio of the GMTs (FLUCELVAX / AGRIFLU) was > 0.67; and the lower limit of the two-sided 95% CI for the difference between the seroconversion rates (FLUCELVAX and AGRIFLU) was > -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 Comparator**
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 Rates*** (FLUCELVAX - Agriflu) -1% (-7, 6) 3% (-2, 9) 7% (1, 12)
* NCT00492063
** AGRIFLU

REFERENCES

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

5. 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.

6. 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.

7. NCT00264576; see http://clinicaltrials.gov/

Last reviewed on RxList: 11/25/2013
This monograph has been modified to include the generic and brand name in many instances.

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