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Flulaval

"Dec. 3, 2012 -- The U.S. flu season is here -- the earliest start since the "moderately severe" season of 2003.

Just as in 2003, the nasty H3N2 flu bug is causing most cases so far.

"This could be a bad flu year," warned CDC"...

Flulaval

CLINICAL PHARMACOLOGY

Mechanism Of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies 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 titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the antibody titers have been used as a measure of vaccine activity. In some human challenge studies, antibody titers of ≥ 1:40 have been associated with protection from influenza illness in up to 50% of subjects.1,2 Antibody against one influenza virus type or subtype confers little or no protection against another virus. 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 virological basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinins of strains (i.e., typically 2 type A and 1 type B), representing the influenza viruses likely to circulate in the United States in the upcoming winter.

Annual revaccination is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.

Clinical Studies

The effectiveness of FLULAVAL was demonstrated based on clinical endpoint efficacy data for FLULAVAL QUADRIVALENT (Influenza Vaccine), clinical endpoint efficacy data for FLULAVAL, and on an evaluation of serum HI antibody responses to FLULAVAL. FLULAVAL QUADRIVALENT, an inactivated influenza vaccine that contains the hemagglutinins of two influenza A subtype viruses and two influenza type B viruses, is manufactured according to the same process as FLULAVAL.

Efficacy Against Influenza

Efficacy Trial in Children

The efficacy of FLULAVAL QUADRIVALENT was evaluated in Study 5, a randomized, observer-blind, non-influenza vaccine-controlled study conducted in 3 countries in Asia, 3 in Latin America, and 2 in the Middle East/Europe during the 2010-2011 influenza season. Healthy subjects 3 through 8 years of age were randomized (1:1) to receive FLULAVAL QUADRIVALENT (N = 2,584), containing A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), and B/Florida/4/2006 (Yamagata lineage) influenza strains, or HAVRIX® (Hepatitis A Vaccine) (N = 2,584), as a control vaccine. Children with no history of influenza vaccination received 2 doses of FLULAVAL QUADRIVALENT or HAVRIX approximately 28 days apart. Children with a history of influenza vaccination received one dose of FLULAVAL QUADRIVALENT or HAVRIX. In the overall population, 52% were male; 60% were Asian, 5% were white, and 35% were of other racial/ethnic groups. The mean age of subjects was 5 years.

Efficacy of FLULAVAL QUADRIVALENT was assessed for the prevention of reverse transcriptase polymerase chain reaction (RT-PCR)-positive influenza A and/or B disease presenting as influenza-like illness (ILI). ILI was defined as a temperature ≥ 100°F in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose, or nasal congestion. Subjects with ILI (monitored by passive and active surveillance for approximately 6 months) had nasal and throat swabs collected and tested for influenza A and/or B by RT-PCR. All RT-PCR-positive specimens were further tested in cell culture. Vaccine efficacy was calculated based on the ATP cohort for efficacy (Table 4).

Table 4: FLULAVAL QUADRIVALENT: Influenza Attack Rates and Vaccine Efficacy Against Influenza A and/or B in Children 3 Through 8 Years of Agea (According toProtocol Cohort for Efficacy)

  Nb nc Influenza Attack Rate % (n/N) Vaccine Efficacy % (CI)
All RT-PCR-Positive Influenza
FLULAVAL QUADRIVALENT 2,379 58 2.4 55.4d (95% CI: 39.1, 67.3)
HAVRIXe 2,398 128 5.3
All Culture-Confirmed Influenzaf
FLULAVAL QUADRIVALENT 2,379 50 2.1 55.9 (97.5% CI: 35.4, 69.9)
HAVRIXe 2,398 112 4.7
Antigenically Matched Culture-Confirmed Influenza
FLULAVAL QUADRIVALENT 2,379 31 1.3 45.1g (97.5% CI: 9.3, 66.8)
HAVRIXe 2,398 56 2.3 -
CI = Confidence Interval; RT-PCR = reverse transcriptase polymerase chain reaction.
a Study 5: NCT01218308.
b According to protocol cohort for efficacy included subjects who met all eligibility criteria, were successfully contacted at least once post-vaccination, and complied with the protocolspecified efficacy criteria.
c Number of influenza cases.
d Vaccine efficacy for FLULAVAL QUADRIVALENT met the pre-defined criterion of > 30% for the lower limit of the 2-sided 95% CI.
e Hepatitis A Vaccine used as a control vaccine.
fOf 162 culture-confirmed influenza cases, 108 (67%) were antigenically typed (87 matched; 21 unmatched); 54 (33%) could not be antigenically typed [but were typed by RT-PCR and nucleic acid sequence analysis: 5 cases A (H1N1) (5 with HAVRIX), 47 cases A (H3N2) (10 with FLULAVAL QUADRIVALENT; 37 with HAVRIX), and 2 cases B Victoria (2 with HAVRIX)].
g Since only 67% of cases could be typed, the clinical significance of this result is unknown.

In an exploratory analysis by age, vaccine efficacy against RT-PCR-positive influenza A and/or B disease presenting as ILI was evaluated in subjects 3 through 4 years of age and 5 through 8 years of age; vaccine efficacy was 35.3% (95% CI: -1.3, 58.6) and 67.7% (95% CI: 49.7, 79.2), respectively. As the study lacked statistical power to evaluate efficacy within age subgroups, the clinical significance of these results is unknown.

As a secondary objective in the study, subjects with RT-PCR-positive influenza A and/or B were prospectively classified based on the presence of adverse outcomes that have been associated with influenza infection (defined as fever > 102.2°F/39.0°C, physician-verified shortness of breath, pneumonia, wheezing, bronchitis, bronchiolitis, pulmonary congestion, croup and/or acute otitis media, and/or physician-diagnosed serious extra-pulmonary complications, including myositis, encephalitis, seizure and/or myocarditis).

The risk reduction of fever > 102.2°F/39.0°C associated with RT-PCR-positive influenza was 71.0% (95% CI: 44.8, 84.8) based on the ATP cohort for efficacy [FLULAVAL QUADRIVALENT (n = 12/2,379); HAVRIX (n = 41/2,398)]. The other pre-specified adverse outcomes had too few cases to calculate a risk reduction. The incidence of these adverse outcomes is presented in Table 5.

Table 5: FLULAVAL QUADRIVALENT: Incidence of Adverse Outcomes Associated With RT-PCR-Positive Influenza in Children 3 Through 8 Years of Agea (Total Vaccinated Cohort)b

Adverse Outcomed FULAVAL QUADRIVALENT
N = 2,584
HAVRIXc
N = 2,584
Number of Events Number of Subjectse % Number of Events Number of Subjectse %
Fever > 102.2°F/39.0°C 16f 15 0.6 51f 50 1.9
Shortness of breath 0 0 0 5 5 0.2
Pneumonia 0 0 0 3 3 0.1
Wheezing 1 1 0 1 1 0
Bronchitis 1 1 0 1 1 0
Pulmonary congestion 0 0 0 1 1 0
Acute otitis media 0 0 0 1 1 0
Bronchiolitis 0 0 0 0 0 0
Croup 0 0 0 0 0 0
Encephalitis 0 0 0 0 0 0
Myocarditis 0 0 0 0 0 0
Myositis 0 0 0 0 0 0
Seizure 0 0 0 0 0 0
a Study 5: NCT01218308.
b Total vaccinated cohort included all vaccinated subjects for whom data were available.
c Hepatitis A Vaccine used as a control vaccine.
d In subjects who presented with more than one adverse outcome, each outcome was counted in the respective category.
e Number of subjects presenting with at least one event in each group.
fOne subject in each group had sequential influenza due to influenza type A and type B viruses.

Efficacy Trial in Adults

The efficacy of FLULAVAL was evaluated in a randomized, double-blind, placebo-controlled study conducted in the United States during the 2005-2006 and 2006-2007 influenza seasons (Study 3). Efficacy of FLULAVAL was defined as the prevention of culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains, compared with placebo. Healthy subjects 18 through 49 years of age were randomized (1:1); a total of 3,783 subjects received FLULAVAL and 3,828 subjects received placebo [see ADVERSE REACTIONS]. Subjects were monitored for influenza-like illnesses (ILI) starting 2 weeks postvaccination and for duration of approximately 7 months thereafter. Culture-confirmed influenza was assessed by active and passive surveillance of ILI. Influenza-like illness was defined as illness sufficiently severe to limit daily activity and including cough, and at least one of the following: Fever > 99.9°F, nasal congestion or runny nose, sore throat, muscle aches or arthralgia, headache, feverishness or chills. After an episode of ILI, nose and throat swab samples were collected for analysis; attack rates and vaccine efficacy were calculated using the per protocol cohort (Table 6). Of note, the 1.2% attack rate in the placebo group for cultureconfirmed, antigenically matched strains was lower than expected, contributing to a wide confidence interval for the estimate of vaccine efficacy.

Table 6: FLULAVAL: Influenza Attack Rates and Vaccine Efficacy Against Culture- Confirmed Influenza in Adults 18 Through 49 Years of Agea (Per Protocol Cohort)

  Influenza Attack Rates Vaccine Efficacy
  Nb nc % (n/N) % 97.5% CI Lower Limit
Antigenically Matched Strains
FLULAVAL 3,714 23 0.6 46.3 9.8d
Placebo 3,768 45 1.2
All Culture-Confirmed Influenza (Matched, Unmatched, and Untyped)
FLULAVAL 3,714 30 0.8 49.3 20.3
Placebo 3,768 60 1.6
CI = Confidence Interval.
a Study 3: NCT00216242.
b Per Protocol Cohort for efficacy included subjects with no protocol deviations considered to compromise efficacy data.
c Number of influenza cases.
dLower limit of the one-sided 97.5% CI for vaccine efficacy against influenza due to antigenically matched strains was less than the pre-defined success criterion of ≥ 35%.

Immunological Evaluation

Adults

Study 1 was a randomized, blinded, active-controlled US study performed in healthy adults 18 through 64 years of age (N = 1,000). A total of 721 subjects received FLULAVAL, and 279 received a US-licensed trivalent, inactivated influenza vaccine, FLUZONE (manufactured by Sanofi Pasteur SA), intramuscularly; 959 subjects had complete serological data and no major protocol deviations [see ADVERSE REACTIONS].

Analyses of immunogenicity (Table 7) were performed for each hemagglutinin (HA) antigen contained in the vaccine: 1) assessment of the lower bounds of 2-sided 95% confidence intervals for the proportion of subjects with HI antibody titers of ≥ 1:40 after vaccination, and 2) assessment of the lower bounds of 2-sided 95% confidence intervals for rates of seroconversion (defined as a 4-fold increase in post-vaccination HI antibody titer from prevaccination titer ≥ 1:10, or an increase in titer from < 1:10 to ≥ 1:40). The pre-specified success criteria for HI titer ≥ 1:40 was 70% and for seroconversion rate was 40%. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved an HI titer of ≥ 1:40 exceeded the pre-defined criteria for the A strains. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved seroconversion exceeded the pre-defined criteria for all 3 strains.

Table 7: Immune Responses to Each Antigen 21 Days After Vaccination With FLULAVALa in Adults 18 Through 64 Years of Age (Per Protocol Cohort)b

HI titers ≥ 1:40 FLULAVAL
N = 692
% of Subjects (95% CI)
Pre-vaccination Post-vaccination
A/New Caledonia/20/99 (H1N1) 24.6 96.5 (94.9, 97.8)
A/Wyoming/03/03 (H3N2) 58.7 98.7 (97.6, 99.4)
B/Jiangsu/10/03 5.4 62.9 (59.1, 66.5)
Seroconversionc to:
A/New Caledonia/20/99 (H1N1) 85.6 (82.7, 88.1)
A/Wyoming/03/03 (H3N2) 79.3 (76.1, 82.3)
B/Jiangsu/10/03 58.4 (54.6, 62.1)
HI = hemagglutination inhibition; CI = Confidence Interval.
a Results obtained following vaccination with FLULAVAL manufactured for the 2004-2005 season.
b Per Protocol Cohort for immunogenicity included subjects with complete pre- and post-dose HI titer data and no major protocol deviations.
c Seroconversion defined as a 4-fold increase in post-vaccination HI antibody titers from prevaccination titer ≥ 1:10, or an increase in titer from < 1:10 to ≥ 1:40.

Study 2 (Immunogenicity Non-Inferiority)

In a randomized, double-blind, activecontrolled US study, immunological non-inferiority of FLULAVAL was compared with a US-licensed trivalent, inactivated influenza vaccine, FLUZONE, manufactured by Sanofi Pasteur SA. A total of 1,225 adults 50 years of age and older in stable health were randomized to receive FLULAVAL or the comparator vaccine intramuscularly [see ADVERSE REACTIONS].

Analyses of immunogenicity were performed for each HA antigen contained in the vaccines: 1) assessment of the lower bounds of 2-sided 95% confidence intervals for the geometric mean antibody titer (GMT) ratio (FLULAVAL/comparator), and 2) assessment of the lower bounds of 2-sided 95% confidence intervals for seroconversion rates (defined as a 4-fold increase in post-vaccination HI antibody titer from pre-vaccination titer ≥ 1:10, or an increase in titer from < 1:10 to ≥ 1:40). Non-inferiority of FLULAVAL to the comparator vaccine was established for all 6 co-primary endpoints (Table 8). Within each age stratum, immunogenicity results were similar between the groups.

Table 8: Immune Responses to Each Antigen 21 Days After Vaccination With FLULAVAL Versus Comparator Influenza Vaccine in Adults 50 Years of Age and Oldera (Per Protocol Cohort)b

  FLULAVAL
N = 592
Active Comparatorc
N = 595
 
GMTs Against GMT (95% CI) GMT (95% CI) GMT Ratiod (95% CI)
A/New Caledonia/20/99 (H1N1) 113.4 (104.7, 122.8) 110.2 (101.8, 119.3) 1.03 (0.92, 1.15)
A/New York/55/04 (H3N2) 223.9 (199.5, 251.3) 214.6 (191.3, 240.7) 1.04 (0.89, 1.23)
B/Jiangsu/10/03 82.3 (74.7, 90.6) 97.1 (88.2, 106.8) 0.85 (0.74, 0.97)
Seroconversione to: % of Subjects (95% CI) % of Subjects (95% CI) Difference in Seroconversion Ratesf (95% CI)
A/New Caledonia/20/99 (H1N1) 34 (30.0, 37.6) 32 (28.3, 35.9) 2 (-3.7, 7.0)
A/New York/55/04 (H3N2) 83 (80.3, 86.3) 82 (78.4, 84.6) 1 (-2.6, 6.1)
B/Jiangsu/10/03 53 (49.0, 57.1) 56 (51.6, 59.6) -3 (-8.3, 3.1)
GMT = geometric mean antibody titer; CI = Confidence Interval.
a Results obtained following vaccination with influenza vaccines manufactured for the 2005-2006 season.
b Per Protocol Cohort for immunogenicity included subjects with complete pre- and post-dose HI titer data and no major protocol deviations.
c US-licensed trivalent, inactivated influenza vaccine (manufactured by Sanofi Pasteur SA).
dFLULAVAL met non-inferiority criteria based on GMTs (lower limit of 2-sided 95% CI for GMT ratio [FLULAVAL/comparator vaccine] ≥ 0.67).
e Seroconversion defined as a 4-fold increase in post-vaccination HI antibody titer from prevaccination titer ≥ 1:10, or an increase in titer from < 1:10 to ≥ 1:40.
fFLULAVAL met non-inferiority criteria based on seroconversion rates (lower limit of 2-sided 95% CI for difference of FLULAVAL minus the comparator vaccine ≥ -10%).

Children

In Study 4, the immune response of FLULAVAL (N = 987) was compared to FLUZONE, a US-licensed trivalent, inactivated influenza vaccine (N = 979), manufactured by Sanofi Pasteur SA, in an observer-blind, randomized study in children 3 through 17 years of age. The immune responses to each of the antigens contained in FLULAVAL formulated for the 2009-2010 season were evaluated in sera obtained after one or 2 doses of FLULAVAL and were compared to those following the comparator influenza vaccine [see ADVERSE REACTIONS].

The non-inferiority endpoints were geometric mean antibody titers (GMTs) adjusted for baseline, and the percentage of subjects who achieved seroconversion, defined as at least a 4-fold increase in serum HI titer over baseline to > 1:40, following vaccination, performed on the According-to-Protocol (ATP) cohort. FLULAVAL was non-inferior to the comparator influenza for all strains based on adjusted GMTs and seroconversion rates (Table 9).

Table 9: Immune Responses to Each Antigen 28 Days After Last Vaccination With FLULAVAL Versus Comparator Influenza Vaccine in Children 3 Through 17 Years of Agea (According to Protocol Cohort for Immunogenicity)b

  FLULAVAL Active Comparatorc  
GMTs Against N = 987
(95% CI)
N = 979
(95% CI)
GMT Ratiod (95% CI)
A/Brisbane (H1N1) 320.9 (298.3, 345.2) 329.4 (306.8, 353.7) 1.03 (0.94, 1.13)
A/Uruguay (H3N2) 414.7 (386.5, 444.9) 451.9 (423.8, 481.8) 1.05 (0.96, 1.13)
B/Brisbane 213.7 (198.5, 230.1) 200.2 (186.1, 215.3) 0.93 (0.85, 1.02)
Seroconversione to: N = 987 % (95% CI) N = 978 % (95% CI) Difference in Seroconversion Ratef (95% CI)
A/Brisbane (H1N1) 59.8 (56.6, 62.9) 58.2 (55.0, 61.3) -1.6 (-5.9, 2.8)
A/Uruguay (H3N2) 68.2 (65.2, 71.1) 66.2 (63.1, 69.1) -2.0 (-6.1, 2.1)
B/Brisbane 81.1 (78.5, 83.5) 78.6 (75.9, 81.2) -2.4 (-6.0, 1.1)
GMT = geometric mean antibody titer; CI = Confidence Interval.
a Results obtained following vaccination with influenza vaccines formulated for the 2009-2010 season.
b According to protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one study vaccine antigen.
c US-licensed trivalent, inactivated influenza vaccine (Sanofi Pasteur SA).
d FLULAVAL met non-inferiority criteria based on GMTs (upper limit of 2-sided 95% CI for GMT ratio [comparator vaccine/FLULAVAL] ≤ 1.5).
e Seroconversion defined as a 4-fold increase in post-vaccination HI antibody titer from prevaccination titer ≥ 1:10, or an increase in titer from < 1:10 to ≥ 1:40.
f FLULAVAL met non-inferiority criteria based on seroconversion rates (upper limit of 2-sided 95% CI for difference of the comparator vaccine minus FLULAVAL ≤ 10%).

REFERENCES

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

2. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972;70:767-777.

3. Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(RR-8):1-62.

Last reviewed on RxList: 9/8/2014
This monograph has been modified to include the generic and brand name in many instances.

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