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Afluria

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Afluria

Afluria

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 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

Clinical Studies

Efficacy Against Laboratory-Confirmed Influenza

In Study 5, the efficacy of AFLURIA was demonstrated in a randomized, observer-blind, placebo-controlled study conducted in 15,044 subjects. Healthy subjects 18 to less than 65 years of age were randomized in a 2:1 ratio to receive a single dose of AFLURIA (enrolled subjects: 10,033; evaluable subjects: 9,889) or placebo (enrolled subjects: 5,011; evaluable subjects: 4,960). The mean age of all randomized subjects was 35.5 years. 54.4% were female and 90.2% were White. Laboratory-confirmed influenza was assessed by active and passive surveillance of influenza-like illness (ILI) beginning 2 weeks post-vaccination until the end of the influenza season, approximately 6 months post-vaccination. ILI was defined as at least one respiratory symptom (e.g., cough, sore throat, nasal congestion) and at least one systemic symptom (e.g., oral temperature of 100.0°F or higher, feverishness, chills, body aches). Nasal and throat swabs were collected from subjects who presented with an ILI for laboratory confirmation by viral culture and real-time reverse transcription polymerase chain reaction. Influenza virus strain was further characterized using gene sequencing and pyrosequencing.

Attack rates and vaccine efficacy, defined as the relative reduction in the influenza infection rate for AFLURIA compared to placebo, were calculated using the per protocol population. Vaccine efficacy against laboratory-confirmed influenza infection due to influenza A or B virus strains contained in the vaccine was 60% with a lower limit of the 95% CI of 41% (Table 5).

Table 5: Laboratory-confirmed Influenza Infection Rate and Vaccine Efficacy in Adults 18 to less than 65 Years of Age (Study 5)

  Subjects* Laboratory-confirmed Influenza Cases Influenza Infection Rate Vaccine Efficacy†
N n n/N % % Lower Limit of the 95% CI
Vaccine-matched Strains
AFLURIA 9889 58 0.59 60 41
Placebo 4960 73 1.47
Any Influenza Virus Strain
AFLURIA 9889 222 2.24 42 28
Placebo 4960 192 3.87
Abbreviations: CI, confidence interval
*The Per Protocol Population was identical to the Evaluable Population in this study.
†Vaccine efficacy = 1 minus the ratio of AFLURIA/placebo infection rates. The objective of the study was to demonstrate that the lower limit of the CI for vaccine efficacy was greater than 40%.

Immunogenicity in Children

Study 1 was a randomized, observer-blind, comparator-controlled study to evaluate the immunological non-inferiority of AFLURIA to a U.S.-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur, Inc.) in subjects 6 months to less than 18 years of age. Results are presented for children 5 to less than 18 years of age (Table 6). A total of 832 subjects (aged 5 to less than 18 years) were enrolled. Subjects were randomized in a 1:1 ratio to receive AFLURIA (enrolled subjects: 417; evaluable subjects: 383) or the comparator vaccine (enrolled subjects: 415; evaluable subjects: 383).

Children 6 months to less than 9 years of age with no history of influenza vaccination received 2 doses approximately 28 days apart. Children 6 months to less than 9 years of age with a history of influenza vaccination and children 9 years of age and older received 1 dose. Children 6 months to less than 3 years of age received 0.25 mL of AFLURIA or comparator influenza vaccine, and children 3 years of age and older received 0.5 mL of AFLURIA or comparator influenza vaccine. Nearly equal proportions of subjects were male (49.9%) and female (50.1%), and the majority were White (85.0%) or Black (10.3%).

Immunogenicity assessments were performed prior to vaccination and at 21 days after vaccination. The co-primary endpoints were HI Geometric Mean Titer (GMT) ratios (adjusted for baseline HI titers) and the difference in seroconversion rates for each vaccine strain 21 days after the final vaccination. Pre-specified non-inferiority criteria required that the upper bound of the 2-sided 95% CI of the GMT ratio (Comparator/AFLURIA) did not exceed 1.5 and the upper bound of the 2-sided 95% CI of the seroconversion rate difference (Comparator minus AFLURIA) did not exceed 10.0% for each strain. As shown in Table 6, non-inferiority of AFLURIA to the comparator vaccine was demonstrated in the per protocol population for influenza A subtypes A(H1N1) and A(H3N2), but not for influenza type B. For influenza type B, non-inferiority was demonstrated for HI GMTs, but not for seroconversion rates. Note that the study was powered to assess the pre-specified non-inferiority criteria based on 1400 evaluable subjects. Analysis of the 761 subjects aged 5 to less than 18 years reduced the power of the study and widened the confidence intervals. In the pre-specified analysis, AFLURIA was not inferior to the comparator vaccine for all three virus strains. Post hoc analyses of immunogenicity by gender did not demonstrate significant differences between males and females. The study was not sufficiently diverse to assess differences between races or ethnicities.

Table 6: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of AFLURIA to a U.S. Licensed Comparator, Subjects 5 to less than 18 Years of Age (Study 1)

Strain Post-vaccination GMT * GMT Ratio Seroconversion %† Difference Met both pre-defined noninferiority criteria? ‡
Comparator
N=381
AFLURIA
N=380
Comparator over AFLURIA (95% CI) Comparator
N=381
AFLURIA
N=380
Comparator minus AFLURIA (95% CI)
A(H1N1) 526.2 507.4 1.03
(0.88, 1.21)
62.7 62.6 0.1
(-6.8, 7.0)
Yes
A(H3N2) 1060.0 961.3 1.07
(0.94, 1.23)
72.2 69.7 2.4
(-4.0, 8.9)
Yes
B 123.3 110.1 1.10
(0.94, 1.29)
75.1 70.0 5.1
(-1.3, 11.4)
No
Abbreviations: CI, confidence interval; GMT, geometric mean titer.
*GMT ratios are adjusted for baseline HI titers
†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.
‡Note that the study was powered to assess the pre-specified non-inferiority criteria based on 1400 evaluable subjects.

Immunogenicity in Adults and Older Adults

Two randomized, controlled clinical studies of AFLURIA evaluated the immune responses by measuring HI antibody titers to each virus strain in the vaccine in adults. In these studies, post-vaccination immunogenicity was evaluated on sera obtained 21 days after administration of a single dose of AFLURIA.

Study 4 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 placebo). Subjects who received AFLURIA were vaccinated using either the preservative-free or thimerosal-containing presentation. The evaluable population consisted of 1,341 subjects (1,077 in the AFLURIA group and 264 in the placebo group). The mean age of the entire evaluable population receiving AFLURIA was 38 years. 62.5% of subjects were female, 81.3% were White, 12.1% were Black, and 6.2% were Asian. Serum HI antibody responses to AFLURIA met the pre-specified co-primary endpoint criteria for all three virus strains (Table 7). Similar responses were observed between genders. The study was not sufficiently diverse to assess immunogenicity by race or ethnicity.

Table 7: Serum Antibody Responses in Subjects 18 through 64 Years of Age Receiving AFLURIA (Study 4)

Strain Variable AFLURIA
N=1077 value (95% CI)
Placebo
N=264 value (95% CI)
A(H1N1)
* HI Titer ≥ 1:40 97.8% (96.7, 98.6) 74.6% (68.9, 79.8)
Seroconversion Rate (%)† 48.7% (45.6, 51.7) 2.3% (0.8, 4.9)
A(H3N2)
* HI Titer ≥ 1:40 99.9% (99.5, 100.0) 72.0% (66.1, 77.3)
Seroconversion Rate (%)† 71.5% (68.7, 74.2) 0.0% (N/A)
B
* HI Titer ≥ 1:40 94.2% (92.7, 95.6) 47.0% (40.8, 53.2)
Seroconversion Rate (%)† 69.7% (66.9, 72.5) 0.4% (< 0.1, 2.1)
*HI 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.
†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. Lower bound of 95% CI for seroconversion should be > 40% for the study population.

Study 6 was a randomized, observer-blind, comparator-controlled study that enrolled 1,268 subjects 65 years of age and older (Table 8). This study compared the immune response following administration of AFLURIA to that following a US-licensed trivalent inactivated influenza vaccine (manufactured by Sanofi Pasteur SA). Subjects were randomized in a 1:1 ratio to receive a single vaccination of AFLURIA (enrolled subjects: 631; evaluable subjects: 605) or the comparator vaccine (enrolled subjects: 637; evaluable subjects: 610). Immunogenicity assessments were performed prior to vaccination and at 21 days after vaccination. Most of the subjects in the per-protocol immunogenicity population were female (56.7%) and White (97.4%). 2.0% were Black and less than 1.0% were of other races or ethnicities.

The co-primary endpoints were HI GMT ratios (adjusted for baseline HI titers) and the difference in seroconversion rates for each vaccine strain 21 days after vaccination. Pre-specified non-inferiority criteria required that the upper bound of the 2-sided 95% CI of the GMT ratio (Comparator/AFLURIA) did not exceed 1.5 and the upper bound of the 2-sided 95% CI of the seroconversion rate difference (Comparator minus AFLURIA) did not exceed 10.0% for each strain. As shown in Table 8, non-inferiority of AFLURIA to the comparator vaccine was demonstrated in the per protocol population for influenza A subtypes A(H1N1) and A(H3N2), but not for influenza type B. For the B strain, non-inferiority was demonstrated for HI GMTs, but not for seroconversion rates. Post hoc analyses of immunogenicity by gender did not demonstrate significant differences between males and females. The study was not sufficiently diverse to assess differences between races or ethnicities.

Table 8: Post-Vaccination HI Antibody GMTs, Seroconversion Rates, and Analyses of Non-Inferiority of AFLURIA to a U.S. Licensed Comparator, Adults 65 Years of Age and Older (Study 6)

Strain Post-vaccination GMT GMT Ratio* Seroconversion %† Difference Met both pre-defined noninferiority criteria?
Comparator
N=610
AFLURIA
N=605
Comparator over AFLURIA
(95% CI)
Comparator
N=610
AFLURIA
N=605
Comparator minus AFLURIA
(95% CI)
A(H1N1) 59.2 59.4 1.04
(0.92, 1.18)
43.0 38.8 4.1
(-1.4, 9.6)
Yes
A(H3N2) 337.7 376.8 0.95
(0.83, 1.08)
68.7 69.4 -0.7
(-5.9, 4.5)
Yes
B 33.4 30.4 1.12
(1.01, 1.25)
34.4 29.3 5.2
(-0.1, 10.4)
No
Abbreviations: CI, confidence interval; GMT, geometric mean titer.
*Post-vaccination GMTs were adjusted for baseline HI titers.
†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.

REFERENCES

1. Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59 (RR-8):1-62.

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, et al. The Role of Serum Hemagglutination-Inhibiting Antibody in Protection against Challenge Infection with Influenza A2 and B Viruses. J Hyg Camb 1972;70:767-777.

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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