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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

Clinical Studies

Efficacy Against Culture-Confirmed Influenza

The efficacy of FLULAVAL was evaluated in a randomized, double-blind, placebo-controlled study conducted in the United States during the 2005-2006 and 2006-2007 influenza seasons (Study 3). Efficacy of FLULAVAL was defined as the prevention of culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains, compared with placebo. Healthy subjects 18 to 49 years of age were randomized (1:1); a total of 3,783 subjects received FLULAVAL and 3,828 subjects received placebo [see ADVERSE REACTIONS]. Subjects were monitored for influenza-like illnesses (ILI) starting 2 weeks post-vaccination and for duration of approximately 7 months thereafter. Culture-confirmed influenza was assessed by active and passive surveillance of ILI. Influenza-like illness was defined as illness sufficiently severe to limit daily activity and including cough, and at least one of the following: Fever > 99.9°F, nasal congestion or runny nose, sore throat, myalgia or arthralgia, headache, feverishness or chills. After an episode of ILI, nose and throat swab samples were collected for analysis; attack rates and vaccine efficacy were calculated using the per protocol cohort (Table 2).

Table 2: Vaccine Efficacy Against Culture-Confirmed Influenza (Per Protocol Cohort)

Immunological Evaluation

Study 1 (Immunogenicity)

In a randomized, active-controlled trial of FLULAVAL, immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of FLULAVAL.

A 1,000-subject randomized, blinded, and controlled US study was performed 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 (manufactured by Sanofi Pasteur SA), intramuscularly; 959 subjects had complete serological data and no major protocol deviations [see ADVERSE REACTIONS].

Analyses of immunogenicity (Table 3) were performed for each hemagglutinin (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 success criteria for HI titer ≥ 1:40 was 70% and for seroconversion rate was 40%. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved an HI titer of ≥ 1:40 exceeded the pre-defined criteria for the A strains. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved seroconversion exceeded the pre-defined criteria for all 3 strains.

Table 3: Serum Hemagglutination-Inhibiting (HI) Antibody Responses to FLULAVAL^a (Per Protocol Cohort^b)

Study 2 (Immunogenicity Non-Inferiority)

In a randomized, double-blind, active-controlled US study, immunological non-inferiority of FLULAVAL was compared with a US-licensed trivalent, inactivated influenza virus vaccine, FLUZONE, manufactured by Sanofi Pasteur SA. A total of 1,225 adults ≥ 50 years of age in stable health were randomized to receive FLULAVAL or the comparator vaccine intramuscularly [see ADVERSE REACTIONS]. Immune responses, specifically HI antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of FLULAVAL or the comparator vaccine.

Analyses of immunogenicity were performed for each HA antigen contained in the vaccines: 1) assessment of the lower bounds of 2-sided 95% confidence intervals for the geometric mean antibody titer (GMT) ratio (FLULAVAL/comparator), and 2) assessment of the lower bounds of 2-sided 95% confidence intervals for seroconversion rates (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). Non-inferiority of FLULAVAL to the comparator vaccine was established for all 6 co-primary endpoints (Table 4). Within each age stratum, immunogenicity results were similar between the groups.

Table 4: Serum Hemagglutination-Inhibiting (HI) Antibody Responses to FLULAVAL Versus Comparator Influenza Vaccine^a (Per Protocol Cohort^b)

REFERENCES

1. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res 2004;103:133-138.

2. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972;70:767-777.

3. Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(RR-8):1-62.

Last reviewed on RxList: 1/10/2012
This monograph has been modified to include the generic and brand name in many instances.