DESCRIPTION
Fluzone (Influenza Virus Vaccine) and Fluzone High-Dose (Influenza Virus Vaccine) are inactivated influenza virus vaccines, for intramuscular use, prepared from influenza viruses propagated in embryonated chicken eggs. The virus-containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is concentrated and purified in a linear sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically disrupted using a non-ionic surfactant, Octylphenol Ethoxylate (Triton® X-100), producing a "split virus". The split virus is further purified and then suspended in sodium phosphate-buffered isotonic sodium chloride solution. The Fluzone High-Dose process uses an additional concentration factor after the ultrafiltration step in order to obtain a higher hemagglutinin (HA) antigen concentration.
Fluzone and Fluzone High-Dose are clear and slightly opalescent in color. Antibiotics are not used in the manufacture of Fluzone or Fluzone High-Dose. The tip caps of the Fluzone and Fluzone High-Dose prefilled syringes may contain natural rubber latex. Vial presentations of Fluzone do not contain latex.
Fluzone and Fluzone High-Dose are standardized according to United States Public Health Service (USPHS) requirements and are formulated to contain the amount of HA per 0.5 mL dose (see Table 5) for each of the three influenza strains recommended for the 2010-2011 Northern Hemisphere influenza season: A/California/07/2009 X-179A (H1N1), A/Victoria/210/2009 X-187 (an A/Perth/16/2009 — like virus) (H3N2), and B/Brisbane/60/2008. (1)
Table 5: Fluzone and Fluzone High-Dose Presentations
|
Quantity
(per dose) |
| Component |
Fluzone Pediatric |
Fluzone |
Fluzone High-Dose |
| (0.25mL Prefilled Syringe) |
|
(0.5 mL Prefilled Syringe) |
|
Active Substance: Split influenza virus, inactivated strains per United States Public Health Service (USPHS) requirement:
|
22.5 mcg HA total |
45 mcg HA total |
180 mcg HA total |
| A (H1N1) |
7.5 mcg HA |
15 mcg HA |
60 mcg HA |
| A (H3N2) |
7.5 mcg HA |
15 mcg HA |
60 mcg HA |
| B |
7.5 mcg HA |
15 mcg HA |
60 mcg HA |
|
Other:
|
|
|
|
| Sodium phosphate-buffered isotonic sodium chloride solution |
QS
to appropriate volume |
QS to appropriate volume |
QS to appropriate volume |
| Formaldehyde |
≤50 mcg |
≤100 mcg |
≤100 mcg |
| Octylphenol Ethoxylate |
≤50 mcg |
≤100 mcg |
≤250 mcg |
| Gelatin |
0.05% |
0.05% |
None |
| Preservative |
|
|
|
| Single Dose Presentations |
None |
None |
None |
| Multi-Dose Presentation (Thimerosal) |
N/A |
25 mcg mercury |
N/A |
|
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 subjects. (3) (4)
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 (ie, typically two type A and one type B), representing the influenza viruses likely to be circulating in the US in the upcoming winter.
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. (1)
NON-CLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Fluzone and Fluzone High-Dose have not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.
|
CLINICAL STUDIES
Immunogenicity of Fluzone in Children
In a study of 2 doses one month apart of Fluzone (2003-2004) in 31 healthy children 6-36 months of age, 77%, 77%, and 48% achieved post vaccination HI titers of 1:40 or greater for the A/H1, A/H3, and B strains, respectively.
Immunogenicity of Fluzone in Adults
In two observational studies of the immunogenicity of Fluzone, younger adults (median age: 38, range: 19 through 59 years of age) and older adults (median age: 72, range: 61 through 86 years of age) were evaluated. The following results were obtained after vaccination with a single-dose of either the year 1999-2000 (cohort 1999) or 2000-2001 (cohort 2000) formulation of Fluzone. (See Table 6.)
Table 6: Percentage (%) Achieving an HI Titer ≥1:40 and 4-Fold Increase in Younger and Older Adults
| Antigen |
Titer ≥1:40
Percent |
4-Fold Increase
Percent |
| N = Number of participants |
|
A (H3N2)
|
Cohort 1999
|
Younger Adults (N = 60) |
72 |
46 |
|
|
| Older Adults (N = 61) |
70 |
42 |
|
|
Cohort 2000
|
Younger Adults (N = 58) |
79 |
45 |
|
|
| Older Adults (N = 62) |
68 |
44 |
|
A (H1N1)
|
Cohort 1999
|
Younger Adults (N = 60) |
49 |
34 |
|
|
| Older Adults (N = 61) |
38 |
27 |
|
|
Cohort 2000
|
Younger Adults (N = 58) |
54 |
52 |
|
|
| Older Adults (N = 62) |
23 |
39 |
|
B
|
Cohort 1999
|
Younger Adults (N = 60) |
38 |
30 |
|
|
| Older Adults (N = 61) |
10 |
10 |
|
|
Cohort 2000
|
Younger Adults (N = 58) |
38 |
29 |
|
|
| Older Adults (N = 62) |
11 |
5 |
Immunogenicity of Fluzone High-Dose in Adults 65 Years of Age and Older
A total of 3,876 individuals 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone in a phase 3, multi-center, randomized, active-controlled, double blind trial conducted in the US. Of those, 3,851 (2,576 randomized to Fluzone High-Dose and 1,275 randomized to Fluzone) were included in the immunogenicity analysis according to the vaccine they were randomized to receive. (2)
Table 7: Demographic Distribution of Participants in the Phase 3 Trial
|
Fluzone High-Dose
(N=2576) |
Fluzone
(N=1275) |
| N = Number of participants in the immunogenicity analysis set |
|
Gender (Percent)
|
|
|
| Female |
51.3 |
54.7 |
| Male |
48.7 |
45.3 |
|
Age (Years)
|
|
|
Mean (min, max)
75 years and older (%) |
72.9 (65, 97)
35% |
72.9 (65, 94)
36% |
|
Race (Percent)
|
|
|
| Asian |
0.3 |
0.5 |
| American Indian or Alaska Native |
0.1 |
0.0 |
| Black |
2.7 |
2.7 |
| Caucasian |
91.7 |
92.9 |
| Hispanic |
4.8 |
3.7 |
| Native Hawaiian or other Pacific Islander |
0.1 |
0.1 |
| Other |
0.3 |
0.2 |
The primary endpoint of the study was HI titer 28 days after vaccination. Pre-specified statistical superiority criteria required that (1) the lower limit (LL) of the 2-sided 95% CI of the GMT ratio [Fluzone High-Dose/Fluzone] be greater than 1.50 for at least two of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated (LL>0.67), and that (2) the lower limit of the 2-sided 95% CI of the seroconversion rate difference [Fluzone High-Dose - Fluzone] be greater than 10% for at least two of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated (LL>-10%). As shown in Table 8, statistically superior HI titers after vaccination with Fluzone High-Dose compared to standard dose Fluzone were demonstrated for two of the three influenza strains. There are no data demonstrating clinically relevant prevention of culture-confirmed influenza or its complications after vaccination with Fluzone High-Dose compared to standard dose Fluzone in individuals 65 years of age and older.
Table 8: GMT Ratios and Seroconversion Rates following Vaccination with Fluzone High-Dose
|
GMT |
GMT
Ratio |
Seroconversion %Seroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination (day 28) titer ≥1:40 or a 4-fold increase for those with pre-vaccination titer ≥1:10.
|
Difference |
Met Both Pre-defined Endpoints?Predefined superiority endpoint for seroconversion: the lower limit of the two-sided 95% CI of the difference of the seroconversion rates (Fluzone High-Dose minus Fluzone) is >10%. Predefined superiority endpoint for GMT ratio: the lower limit of the 95% CI for GMT ratio (Fluzone High-Dose divided by Fluzone) is >1.5.
|
| Influenza Strain |
Fluzone
High-Dose
N
=2576 |
Fluzone
N=1275 |
Fluzone High-Dose over Fluzone (95% CI) |
Fluzone
High-Dose
N=2576 |
Fluzone
N=1275 |
Fluzone High-Dose minus Fluzone (95% CI) |
|
| Note: As defined in the study protocol: |
|
A (H1N1)
|
115.8 |
67.3 |
1.7
(1.6; 1.8) |
48.6 |
23.1 |
25.4
(22.4; 28.5) |
Yes |
|
A (H3N2)
|
608.9 |
332.5 |
1.8
(1.7; 2.0) |
69.1 |
50.7 |
18.4
(15.1; 21.7) |
Yes |
|
B
|
69.1 |
52.3 |
1.3
(1.2; 1.4) |
41.8 |
29.9 |
11.8
(8.6; 15.0) |
No |
|
