May 4, 2016
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Influenza A H1N1 Monovalent Vaccine

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Influenza A H1N1 Monovalent Vaccine

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.3,4

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.

Clinical Studies

CSL's Influenza A (H1N1) 2009 Monovalent Vaccine and seasonal trivalent Influenza Virus Vaccine (AFLURIA) are manufactured by the same process. Data in this section were obtained in clinical studies conducted with AFLURIA.

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 5). 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 5: Study 1 – Serum HI Antibody Responses in Subjects ≥ 18 to < 65 Years Receiving AFLURIA

Treatment Arm Number  Enrolled/  Evaluable Vaccine  Strain Seroconversion Rate (95% CI) HI Titer ≥ 1:40†
(95% CI)
All active AFLURIA influenza vaccine formulations* 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)
* 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.
† 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.
‡ Active formulations include aggregated results for the single-dose (preservative-free) and multi-dose formulations of AFLURIA.

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 6.

Table 6: Study 2 – Serum HI Antibody Responses in Subjects ≥ 65 Years Receiving AFLURIA

Number of Subjects Vaccine Strain Seroconversion Rate* (95% CI) HI Titer ≥ 1:40† (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)
* 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 > 30% for the study population.
† 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 > 60% for the study population.

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 7.

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 7: Study 4 – Serum HI Antibody Responses in Subjects ≥ 6 months to < 9 Years Receiving AFLURIA

Vaccine  Strain Vaccine Dose Seroconversion Rate*
(lower 95% CI)
HI Titer ≥ 1:40†

(lower 95% CI)
Subjects ≥ 6 months to < 3 years
n=143‡
n=139§
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)
* 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).
† 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).
‡ Evaluable population post-dose 1.
§ Evaluable population post-dose 2.

REFERENCES

1. Centers for Disease Control and Prevention. Serum Cross-Reactive Antibody Response to a Novel Influenza A (H1N1) Virus After Vaccination with Seasonal Influenza Vaccine. MMWR 2009;58 (19): 521-524.

2. Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2009;58 (RR-8):1-52.

3. Hannoun C, Megas F, Piercy J. Immunogenicity and Protective Efficacy of Influenza Vaccination. Virus Res 2004;103:133-138.

4. 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: 11/30/2015
This monograph has been modified to include the generic and brand name in many instances.

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