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Flulaval (Influenza Virus Vaccine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

FLULAVAL, Influenza Virus Vaccine, for intramuscular injection, is a trivalent, split-virion, inactivated influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens' eggs. Each of the influenza virus strains is produced and purified separately. The virus is inactivated with ultraviolet light treatment followed by formaldehyde treatment, purified by centrifugation, and disrupted with sodium deoxycholate.

FLULAVAL is a sterile, translucent to whitish opalescent suspension in a phosphate-buffered saline solution that may sediment slightly. The sediment resuspends upon shaking to form a homogeneous suspension. FLULAVAL has been standardized according to USPHS requirements for the 2010-2011 influenza season and is formulated to contain 45 mcg hemagglutinin per 0.5-mL dose in the recommended ratio of 15 mcg HA of each of the following 3 strains: A/California/7/2009 NYMC X-179A (H1N1), A/Victoria/210/2009 NYMC X-187 (H3N2) (an A/Perth/16/2009-like virus), and B/Brisbane/60/2008. Thimerosal, a mercury derivative, is added as a preservative. Each dose contains 25 mcg mercury. Each dose may also contain residual amounts of egg proteins (≤1 mcg ovalbumin), formaldehyde (≤25 mcg), and sodium deoxycholate (≤50 mcg). Antibiotics are not used in the manufacture of this vaccine.

The vial stopper does not contain 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) viruses and influenza B viruses have been in global circulation. Specific levels of HI antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the antibody titers have been used as a measure of vaccine activity. In some human challenge studies, antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.1,2 Antibody against one influenza virus type or subtype confers little or no protection against another virus. 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 virological basis for seasonal epidemics and the reason for the usual change of one or more new strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinins of strains (i.e., typically 2 type A and 1 type B), representing the influenza viruses likely to circulate in the United States in the upcoming winter.

Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.3

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

CLINICAL STUDIES

In 2 randomized, active-controlled trials of FLULAVAL, the immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of FLULAVAL. No controlled trials demonstrating a decrease in influenza disease after vaccination with FLULAVAL have been performed.

A 1,000-subject randomized, blinded, and controlled study was performed in the United States in 18- to 64-year-old healthy adults. A total of 721 subjects received FLULAVAL, and 279 received a US-licensed trivalent, inactivated influenza virus vaccine (FLUZONE); 959 subjects had complete serological data and no major protocol deviations. Among recipients of FLULAVAL, 57.4% were women. The mean age of recipients of FLULAVAL was 37.9 years; 80.4% were 18 to 49 years of age and 19.6% were 50 to 64 years of age.

A second, randomized, blinded, and controlled study which enrolled 658 subjects 50 years of age and older (stratified by age <65 and ≥65 years) was conducted in Canada. This study included elderly persons with medically controlled chronic high-risk diagnoses who were clinically stable. This study compared 4 vaccine groups: FLULAVAL, a similar investigational formulation of FLULAVAL with reduced thimerosal, and 2 Canadian-licensed trivalent influenza vaccines. Results from the 2 groups that received FLULAVAL were submitted in support of the US licensure of FLULAVAL. Among these 2 groups, 54.9% of subjects were women. The mean age of recipients of FLULAVAL was 63 years; 53.4% were 50 to 64 years of age and 46.6% were 65 years of age and older.

For both studies, analysis of the following co-primary endpoints (Table 3) were performed for each HA antigen contained in the vaccine: 1) assessment of the lower bounds of 2-sided 95% confidence intervals for the proportion of subjects with HI antibody titers of ≥1:40 after vaccination, and 2) assessment of the lower bounds of 2-sided 95% confidence intervals for rates of seroconversion (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 pre-specified targets for the 2 endpoints varied by study because of age of subjects enrolled. The pre-specified target for endpoint 1) was 70% in the US study and 60% in the Canadian study. For endpoint 2) the pre-specified target was 40% in the US study and 30% in the Canadian study. For the Canadian study, the primary endpoints, as originally designed, were descriptive comparisons of immune response; therefore, a post-hoc analysis of the endpoints, as described above, was performed.

Table 3. Serum Hemagglutination-Inhibiting (HI) Antibody Responses to FLULAVAL in 2 Clinical Trialsa (Per Protocol Cohort)b

a Results obtained following vaccination with FLULAVAL manufactured for the 2004—2005 season.

b Per Protocol Cohort for immunogenicity included subjects with complete pre- and post-dose HI titer data and no major protocol deviations.

c Lower bounds were calculated using Clopper-Pearson method.

d Seroconversion = a 4-fold increase post-vaccination in HI antibody titer from pre-vaccination titer ≥1:10, or an increase in titer from <1:10 to ≥1:40.

e Includes subjects who received FLULAVAL and a similar investigational formulation of FLULAVAL with reduced thimerosal.

US Trial in Adults 18 to 64 years of age

% of Subjects

(lower bound of 2-sided 95% confidence interval)c

FLULAVAL

Primary endpoint met

post-vaccination

N = 692

HI titers ≥1:40 against:

Pre-vaccination

Post-vaccination

A/New Caledonia/20/99 (H1N1)

24.6

96.5 (94.9)

Yes

A/Wyoming/03/03 (H3N2)

58.7

98.7 (97.6)

Yes

B/Jiangsu/10/03

5.4

62.9 (59.1)

No

Seroconversiond to:

A/New Caledonia/20/99 (H1N1)

85.6 (82.7)

Yes

A/Wyoming/03/03 (H3N2)

79.3 (76.1)

Yes

B/Jiangsu/10/03

58.4 (54.6)

Yes

Canadian Trial in Adults ≥50 years of age

% of Subjects

(lower bound of 2-sided 95% confidence interval)c

FLULAVALe

Primary endpoint met

post-vaccination

N = 324

HI titers ≥1:40 against:

Pre-vaccination

Post-vaccination

A/New Caledonia/20/99 (H1N1)

39.5

86.4 (82.2)

Yes

A/Wyoming/03/03 (H3N2)

67.9

99.1 (97.3)

Yes

B/Jiangsu/10/03

10.2

57.1 (51.5)

No

Seroconversiond to:

A/New Caledonia/20/99 (H1N1)

44.8 (39.3)

Yes

A/Wyoming/03/03 (H3N2)

69.1 (63.8)

Yes

B/Jiangsu/10/03

49.1 (43.5)

Yes

Across both studies, serum HI antibody responses to FLULAVAL met the pre-specified seroconversion criteria for all 3 virus strains, and also the pre-specified criterion for the proportion of subjects with HI titers ≥1:40 for both influenza A viruses. In both trials, both FLULAVAL and the comparator vaccine did not meet the pre-specified criterion for the proportion of subjects with HI titers ≥1:40 for the influenza B virus. The clinical relevance of this finding on vaccine-induced protection against illness caused by influenza type B strains is unknown.

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