April 30, 2016
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Fluzone

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Fluzone




CLINICAL PHARMACOLOGY

Mechanism Of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, 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 virus infection. In some human studies, antibody titers ≥ 1:40 have been associated with protection from influenza illness in up to 50% of participants.2,3

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 change of one or more new strains in each year's influenza vaccine. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains representing the influenza viruses likely to be circulating in the US during the influenza season.

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

Clinical Studies

Efficacy Of Fluzone In Children 6 through 24 Months Of Age

A randomized, double-blind, placebo-controlled study was conducted at a single US center during the 1999-2000 (Year 1) and 2000-2001 (Year 2) influenza seasons. The intent-to-treat analysis set included a total of 786 children 6 through 24 months of age. Participants received two doses of either Fluzone (N = 525) or a placebo (N = 261). Among all randomized participants in both years, the mean age was 13.8 months; 52.5% were male, 50.8% were Caucasian, 42.0% were Black, and 7.2% were of other racial groups. Cases of influenza were identified through active and passive surveillance for influenza-like illness or acute otitis media and confirmed by culture. Influenza-like illness was defined as fever with signs or symptoms of an upper respiratory infection. Vaccine efficacy against all influenza viral types and subtypes was a secondary endpoint and is presented in Table 7.

Table 7: Estimated Efficacy of Fluzone Against Culture-Confirmed Influenza in Children Aged 6 through 24 Months during the 1999-2000 and 2000-2001 Influenza Seasons - Intentto- Treat Analysis Seta

Year Fluzoneb Placeboc Fluzone vs. Placebo
nd Ne Rate (n/N)f (95% CI) nd Ne Rate (n/N)f (95% CI) Relative Risk (95% CI) Percent Relative Reductiong (95% CI)
Year 1h (1999- 2000) 15 273 5.5 (3.1; 8.9) 22 138 15.9 (10.3; 23.1) 0.34 (0.18; 0.64) 66 (36; 82)
Year 2 i (2000- 2001) 9 252 3.6 (1.6; 6.7) 4 123 3.3 (0.9; 8.1) 1.10 (0.34; 3.50) -10 (-250; 66)
aThe intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinated
bFluzone: 1999-2000 formulation containing A/Beijing/262/95 (H1N1), A/Sydney/15/97 (H3N2), and B/Yamanashi/166/98 (Yamagata lineage) and 2000-2001 formulation containing A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Yamanashi/166/98 (Yamagata lineage)
c“Placebo: 0.4% NaCl
dn is the number of participants with culture-confirmed influenza for the given year of study as listed in the first column
eN is the number of participants randomly assigned to receive Fluzone or placebo for the given year of study as listed in the column headers (intent-to-treat analysis set)
fRate (%) = (n/N) * 100
gRelative reduction in vaccine efficacy was defined as (1-relative risk) x 100
hIncludes all culture confirmed influenza cases throughout the study duration for Year 1 (12 months of follow-up)
iIncludes all culture-confirmed influenza cases throughout the study duration for Year 2 (6 months of follow-up)

Efficacy Of Fluzone In Adults

A randomized, double-blind, placebo-controlled study was conducted in a single US center during the 2007-2008 influenza season. Participants received one dose of either Fluzone vaccine (N = 813), an active comparator (N = 814), or placebo (N = 325). The intent-to-treat analysis set included 1138 healthy adults who received Fluzone or placebo. Participants were 18 through 49 years of age (mean age was 23.3 years); 63.3% were female, 83.1% were Caucasian, and 16.9% were of other racial/ethnic groups. Cases of influenza were identified through active and passive surveillance and confirmed by cell culture and/or real-time polymerase chain reaction (PCR). Influenza-like illness was defined as an illness with at least 1 respiratory symptom (cough or nasal congestion) and at least 1 constitutional symptom (fever or feverishness, chills, or body aches). Vaccine efficacy of Fluzone against all influenza viral types and subtypes is presented in Table 8.

Table 8: Estimated Efficacy of Fluzone Vaccine Against Influenza in Adults Aged 18 through 49 Years during the 2007-2008 Influenza Season - Intent-to-Treat Analysis Seta

Laboratory- Confirmed Symptomatic Influenza Fluzoneb (N=813)d Placeboc (N=325)d Fluzone vs. Placebo
ne Rate (%)f (95% CI) ne Rate (%)f (95% CI) Relative Risk (95% CI) Percent Relative Reductiong (95% CI)
Positive culture 21 2.6 (1.6; 3.9) 31 9.5 (6.6; 13.3) 0.27 (0.16; 0.46) 73 (54; 84)
Positive PCR 28 3.4 (2.3; 4.9) 35 10.8 (7.6; 14.7) 0.32 (0.20; 0.52) 68 (48; 80)
Positive culture, positive PCR, or both 28 3.4 (2.3; 4.9) 35 10.8 (7.6; 14.7) 0.32 (0.20; 0.52) 68 (48; 80)
aThe intent-to-treat analysis set includes all enrolled participants who were randomly assigned to receive Fluzone or placebo and vaccinated
bFluzone: 2007-2008 formulation containing A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (Victoria lineage)
cPlacebo: 0.9% NaCl
dN is the number of participants randomly assigned to receive Fluzone or placebo
en is the number of participants satisfying the criteria listed in the first column
fRate (%) = (n/N) * 100
gRelative reduction in vaccine efficacy was defined as (1 - relative risk) x 100

Immunogenicity Of Fluzone In Children 6 Months through 8 Years Of Age

In a multi-center study conducted in the US, 68 children 6 months through 35 months of age given two 0.25 mL doses of Fluzone and 120 children 3 years through 8 years of age given two 0.5 mL doses of Fluzone were included in the per-protocol analysis set. The two doses (20062007 formulation) were administered 26 to 30 days apart. Females accounted for 42.6% of the participants in the 6 months through 35 months age group and 53.3% of the participants in the 3 years through 8 years age group. Most participants in the 6 months through 35 months and 3 years through 8 years age groups, respectively, were Caucasian (70.6% and 79.2%), followed by Hispanic (19.1% and 13.3%), and Black (7.4% and 4.2%).

The percentage of participants who received influenza vaccination during the previous influenza season was 54.4% for the 6 months through 35 months age group and 27.5% for the 3 years through 8 years age group. Table 9 shows seroconversion rates and the percentage of participants with an HI titer ≥ 1:40 pre-vaccination and one month following the second dose of Fluzone.

Table 9: Percentage (%) with Pre and Post-Vaccination HI Titers ≥ 1:40 and Seroconversion Following the Second Vaccine Injection with Fluzonea in Children 6 Months Through 35 Months and 3 Years Through 8 Years of Age

Antigen Age Group Pre-Vaccination Titer ≥ 1:40 % (95% CI) Post-Vaccinationb Titer ≥ 1:40 % (95% CI) Seroconversionc % (95% CI)
N=68 (6 to 35 months); N=120 (3 through 8 years)
A (H1N1) 6 through 35 months 11.8 (5.2; 21.9) 92.6 (83.7; 97.6) 88.2 (78.1; 94.8)
3 through 8 years 40.0 (31.2; 49.3) 99.2 (95.4; 100.0) 78.3 (69.9; 85.3)
A (H3N2) 6 through 35 months 29.4 (19.0; 41.7) 100.0 (94.7; 100.0) 91.2 (81.8; 96.7)
3 through 8 years 80.0 (71.7; 86.7) 100.0 (97.0; 100.0) 61.7 (52.4; 70.4)
B 6 through 35 months 1.5 (0.0; 7.9) 20.6 (11.7; 32.1) 20.6 (11.7; 32.1)
3 through 8 years 3.3 (0.9; 8.3) 58.3 (49.0; 67.3) 53.3 (44.0; 62.5)
a Children received two doses of Fluzone administered 26 to 30 days apart, irrespective of previous influenza vaccination history
b Post-vaccination HI titers drawn at 28 days post-dose
c Seroconversion: Paired samples with pre-vaccination HI titer < 1:10 and post-vaccination (28 days post-dose 2) titer ≥ 1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥ 1:10

Immunogenicity Of Fluzone In Adults

Adults 18 through 64 years of age received Fluzone (2008-2009 formulation) in a multi-center trial conducted in the US. For immunogenicity analyses, there were 1287 participants who received Fluzone in the per-protocol analysis set. There were fewer males (35.8%) than females. The mean age was 42.6 years (ranged from 18.2 through 65.0 years). Most participants were Caucasian (80.0%), followed by Hispanic (11.0%), and Black (6.3%). Table 10 shows seroconversion rates at 28 days following vaccination and the percentage of participants with an HI titer ≥ 1:40 prior to vaccination and 28 days following vaccination.

Table 10: Percentage (%) with Pre and Post-Vaccination HI Titers ≥ 1:40 and Seroconversion in Adult Fluzone Recipients 18 Through 64 Years of Age

Antigen Pre-Vaccination Titer ≥ 1:40 % (95% CI)
Nc=1285-1286
Post-Vaccinationa Titer ≥ 1:40 % (95% CI)
Nc=1283-1285
Seroconversionb % (95% CI)
Nc=1283-1285
A (H1N1) 39.1 (36.4; 41.8) 91.7 (90.0; 93.1) 60.5 (57.7; 63.2)
A (H3N2) 33.6 (31.0; 36.2) 91.4 (89.8; 92.9) 74.8 (72.3; 77.1)
B 41.2 (38.5; 44.0) 89.3 (87.4; 90.9) 54.2 (51.4; 56.9)
a Post-vaccination HI titers drawn at 28 days post-dose
b Seroconversion: Paired samples with pre-vaccination HI titer < 1:10 and post-vaccination (28 days post-dose) titer ≥ 1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥ 1:10
c N is the number of vaccinated participants with available data for the immunologic endpoint listed

Immunogenicity Of Fluzone In Geriatric Adults

Adults 65 years of age and older received Fluzone (2006-2007 formulation) in a multi-center trial conducted in the US. For immunogenicity analyses, there were 1275 participants who received Fluzone in the immunogenicity analysis set. Females accounted for 54.7% of participants. The mean age was 72.9 years (ranged from 65 through 94 years of age); 36% of participants were 75 years of age or older. Most participants were Caucasian (92.9%), followed by Hispanic (3.7%), and Black (2.7%). Table 11 shows seroconversion rates at 28 days following vaccination and the percentage of participants with an HI titer ≥ 1:40 prior to vaccination and 28 days following vaccination.

Table 11: Percentage (%) with Pre and Post-Vaccination HI Titers ≥ 1:40 and Seroconversion in Adult Fluzone Recipients 65 Years of Age and Older

Antigen Pre-Vaccination HI Titer ≥ 1:40 % (95% CI)
Nc=1267-1268
Post-Vaccinationa Titer ≥ 1:40 % (95% CI)
Nc=1252
Seroconversionb % (95% CI)
Nc=1248-1249
A (H1N1) 45.9 (43.2; 48.7) 76.8 (74.3; 79.1) 23.1 (20.8; 25.6)
A (H3N2) 68.6 (66.0; 71.2) 96.5 (95.3; 97.4) 50.7 (47.9; 53.5)
B 27.3 (24.9; 29.9) 67.6 (64.9; 70.2) 29.9 (27.4; 32.6)
a Post-vaccination HI titers drawn at 28 days post-dose
b Seroconversion: Paired samples with pre-vaccination HI titer < 1:10 and post-vaccination (28 days post-dose) titer ≥ 1:40 or a minimum 4-fold increase for participants with pre-vaccination titer ≥ 1:10
c N is the number of vaccinated participants with available data for the immunologic endpoint listed

REFERENCES

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 AS, Ward-Gardner A. The role of serum haemagglutinationinhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972;70:767-777.

Last reviewed on RxList: 11/3/2015
This monograph has been modified to include the generic and brand name in many instances.

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