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Afluria (Influenza Virus Vaccine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

AFLURIA, Influenza Virus Vaccine for intramuscular injection, is a sterile, clear, colorless to slightly opalescent suspension with some sediment that resuspends upon shaking to form a homogeneous suspension. AFLURIA is prepared from influenza virus propagated in the allantoic fluid of embryonated chicken eggs. Following harvest, the virus is purified in a sucrose density gradient using a continuous flow zonal centrifuge. The purified virus is inactivated with beta-propiolactone, and the virus particles are disrupted using sodium taurodeoxycholate to produce a "split virion". The disrupted virus is further purified and suspended in a phosphate buffered isotonic solution.

AFLURIA is standardized according to USPHS requirements for the 2010-2011 influenza season and is formulated to contain 45 mcg hemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 15 mcg HA for each of the three influenza strains recommended for the 2010-2011 Northern Hemisphere influenza season: A/California/7/2009, NYMC X-181 (H1N1), A/Victoria/210/2009, NYMC X-187 (H3N2) (an A/Perth/16/2009-like strain), and B/Brisbane/60/2008. A 0.25 mL dose contains 7.5 mcg HA of each of the same three influenza strains.

Thimerosal, a mercury derivative, is not used in the manufacturing process for the single dose presentations; therefore these products contain no preservative. The multi-dose presentation contains thimerosal, added as a preservative; each 0.5 mL dose contains 24.5 mcg of mercury.

A single 0.5 mL dose of AFLURIA contains sodium chloride (4.1 mg), monobasic sodium phosphate (80 mcg), dibasic sodium phosphate (300 mcg), monobasic potassium phosphate (20 mcg), potassium chloride (20 mcg), and calcium chloride (1.5 mcg). From the manufacturing process, each 0.5 mL dose may also contain residual amounts of sodium taurodeoxycholate (≤ 10 ppm), ovalbumin (≤ 1 mcg), neomycin sulfate (≤ 0.2 picograms [pg]), polymyxin B (≤ 0.03 pg), and beta-propiolactone (< 25 nanograms). A single 0.25 mL dose of AFLURIA contains half of these quantities.

The rubber tip cap and plunger used for the preservative-free, single-dose syringes and the rubber stoppers used for the multi-dose vial contain no latex.

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) and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers post-vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza virus. In some human studies, antibody titers of 1:40 or greater 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 limited 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 to one or more new strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the HA of three strains (i.e., typically two type A and one type B) representing the influenza viruses likely to be circulating in the US during the upcoming winter.

Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination and circulating strains of influenza virus change from year to year.1

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

AFLURIA has not been evaluated for carcinogenic or mutagenic potential or for impairment of fertility.

CLINICAL STUDIES

Immunogenicity in the Adult and Geriatric Populations

Three randomized, controlled clinical studies of AFLURIA have evaluated the immune responses by measuring HI antibody titers to each virus strain in the vaccine. In these studies, post-vaccination immunogenicity was evaluated on sera obtained 21 days after administration of AFLURIA. No controlled clinical studies demonstrating a decrease in influenza disease after vaccination with AFLURIA have been performed.

The US study (Study 1) was a randomized, double-blinded, placebo-controlled, multicenter study in healthy subjects ages 18 to less than 65 years. A total of 1,357 subjects were vaccinated (1,089 subjects with AFLURIA and 268 with a thimerosal-containing placebo). Subjects receiving AFLURIA were vaccinated using either a single-dose (preservative-free) or multi-dose (one of three lots) formulation. The evaluable efficacy population consisted of 1,341 subjects (1,077 in the AFLURIA group and 264 in the placebo group) with complete serological data who had not received any contraindicated medications before the post-vaccination immunogenicity assessment. Among the evaluable efficacy population receiving AFLURIA, 37.5% were men and 62.5% were women. The mean age of the entire evaluable population receiving AFLURIA was 38 years; 73% were ages 18 to less than 50 years and 27% were ages 50 to less than 65 years. Additionally, 81% of AFLURIA recipients were White, 12% Black, and 6% Asian.

In Study 1, the following co-primary immunogenicity endpoints were assessed: 1) the lower bounds of the 2-sided 95% confidence intervals (CI) for the proportion of subjects with HI antibody titers of 1:40 or greater after vaccination, which should exceed 70% for each vaccine antigen strain; and 2) the lower bounds of the 2-sided 95% CI for rates of seroconversion (defined as a 4-fold increase in post-vaccination HI antibody titers from pre-vaccination titers of 1:10 or greater, or an increase in titers from less than 1:10 to 1:40 or greater), which should exceed 40% for each vaccine antigen strain.

In subjects ages 18 to less than 65 years, serum HI antibody responses to AFLURIA met the pre-specified co-primary endpoint criteria for all three virus strains (Table 6). Clinical lot-to-lot consistency was demonstrated for the single-dose (preservative-free) and multi-dose formulations of AFLURIA, showing that these formulations elicited similar immune responses.

Table 6: Study 1 — Serum HI Antibody Responses in Subjects ≥ 18 to < 65 Years Receiving AFLURIA
Treatment Arm Number Enrolled/Evaluable Vaccine Strain Seroconversion RateSeroconversion rate is 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. Lower bound of 95% CI for seroconversion should be > 40% for the study population.
(95% CI)
HI Titer ≥ 1:40HI titer ≥ 1:40 is defined as the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40. Lower bound of 95% CI for HI antibody titer ≥ 1:40 should be > 70% for the study population.
(95% CI)
All active AFLURIA influenza vaccine formulationsActive formulations include aggregated results for the single-dose (preservative-free) and multi-dose formulations of AFLURIA. 1089/1077 H1N1 48.7%
(45.6, 51.7)
97.8%
(96.7, 98.6)
H3N2 71.5%
(68.7, 74.2)
99.9%
(99.5, 100.0)
B 69.7%
(66.9, 72.5)
94.2%
(92.7, 95.6)
Placebo 270/264 H1N1 2.3%
(0.8, 4.9)
74.6%
(68.9, 79.8)
H3N2 0.0%
(N/A)
72.0%
(66.1, 77.3)
B 0.4%
(< 0.1, 2.1)
47.0%
(40.8, 53.2)

The UK study (Study 2) was a randomized, controlled study that enrolled 275 healthy subjects ages 65 years and older. This study compared AFLURIA with a European-licensed trivalent inactivated influenza vaccine as an active control. The evaluable efficacy population consisted of 274 subjects (206 in the AFLURIA group and 68 in the control group). Among these subjects, 50% were men and 50% were women, with a mean age of 72 years (range: 65 to 93 years).

The co-primary immunogenicity endpoints for the seroconversion rate and the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40 are presented in Table 7.

Table 7: Study 2 — Serum HI Antibody Responses in Subjects ≥ 65 Years Receiving AFLURIA
Number of Subjects Vaccine Strain Seroconversion RateSeroconversion rate is 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. Lower bound of 95% CI for seroconversion should be > 30% for the study population.
(95% CI)
HI Titer ≥ 1:40HI titer ≥ 1:40 is defined as the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40. Lower bound of 95% CI for HI antibody titer ≥ 1:40 should be > 60% for the study population.
(95% CI)
206 H1N1 34.0% (27.5, 40.9) 85.0% (79.3, 89.5)
H3N2 44.2% (37.3, 51.2) 99.5% (97.3, 100.0)
B 45.6% (38.7, 52.7) 77.7% (71.4, 83.2)

A second UK study (Study 3) was a randomized, controlled study that enrolled 406 healthy subjects ages 18 years and older (stratified by age from 18 to less than 60 years and 60 years and older). This study compared AFLURIA with a European-licensed trivalent inactivated influenza vaccine as an active control. In a post-hoc analysis of different age ranges, among subjects ages 18 to less than 65 years receiving AFLURIA (146 subjects), 47% were men and 53% were women, with a mean age of 48 years for all subjects. Among subjects ages 65 years and older receiving AFLURIA (60 subjects), 53% were men and 47% were women, with a mean age of 71 years.

Analysis of serum HI antibody responses showed that the lower bound of the 95% CI for subjects with HI antibody titers of 1:40 or greater after vaccination exceeded 70% for each strain. HI antibody responses were lower in subjects, ages 65 years and older after administration of AFLURIA. Serum HI antibody responses to the active control were similar to those for AFLURIA in both age groups.

Immunogenicity in a Pediatric Population

An open-label, uncontrolled, multi-center study (Study 4) to evaluate the safety, tolerability and immunogenicity of AFLURIA in children 6 months to 9 years of age was conducted in Australia. The study subjects were subdivided into two groups dependent upon age at time of enrollment. A total of 298 subjects were enrolled, including 151 subjects, 6 months to less than 3 years (mean age 1.7 years with 51.0% females) and 147 subjects, 3 years to less than 9 years (mean age 5 years with 55.1% females).

Two doses of AFLURIA were administered to all subjects, with a 30 day interval between each dose. Children ages 6 months to less than 3 years received two 0.25 mL doses of AFLURIA. Children ages 3 years to less than 9 years were administered two 0.5 mL doses of AFLURIA. Sera for immunological assessment were taken 30 days ( 3) following each vaccination. Immunogenicity endpoints were the seroconversion rate and the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40. The results for each dose are presented in Table 8.

For both age groups, the vaccine met FDA acceptance criteria for immunogenicity developed for healthy adults for all three influenza strains following two doses. These criteria are: 1) that the lower bound of the 2-sided 95% CI for the seroconversion rate should be at least 40%; and 2) the lower bound of the 2-sided 95% CI for the proportion of subjects with a post-vaccination HI titer of ≥ 1:40 should be at least 70%.

Table 8: Study 4 — Serum HI Antibody Responses in Subjects ≥ 6 months to < 9 Years Receiving AFLURIA
Vaccine Strain Vaccine Dose Seroconversion Rate 1
(lower 95% CI)
HI Titer ≥ 1:40 2
(lower 95% CI)
Subjects
≥ 6 months to
< 3 years

n=143 3
n=139 4
H1N1 Dose 1 16.1% (> 11.3) 16.1% (> 11.3)
Dose 2 95.0% (> 90.8) 95.7% (> 91.7)
H3N2 Dose 1 86.0% (> 80.3) 97.9% (> 94.7)
Dose 2 90.6% (> 85.6) 100.0% (> 97.9)
B Dose 1 20.3% (> 14.9) 21.0% (> 15.5)
Dose 2 94.2% (> 89.9) 95.7% (> 91.7)
Subjects
≥ 3 years to
< 9 years

n=144
n=132
H1N1 Dose 1 24.3% (> 18.5) 25.7% (> 19.8)
Dose 2 93.9% (> 89.3) 95.5% (> 91.2)
H3N2 Dose 1 68.1% (> 61.1) 98.6% (> 95.7)
Dose 2 70.5% (> 63.2) 100.0% (> 97.8)
B Dose 1 32.6% (> 26.2) 34.0% (> 27.5)
Dose 2 93.2% (> 88.4) 94.7% (> 90.3)

1 Seroconversion rate is 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. The lower 95% confidence limits were determined. Lower bound of 95% CI for seroconversion was taken as > 40% for the study population (as applied to adults 18 to 64 years of age).
2 HI titer ≥ 1:40 is defined as the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40. The lower 95% confidence limits were determined. Lower bound of 95% CI for HI antibody titer ≥ 1:40 was taken as > 70% for the study population (as applied to adults 18 to 64 years of age).
3 Evaluable population post-dose 1.
4 Evaluable population post-dose 2.

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