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 hemagglutination inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza virus infection. In some human studies, antibody titers ≥ 1:40 have been associated with protection from influenza illness in up to 50% of subjects. (2) (3)

Antibodies against one influenza virus type or subtype confer limited or no protection against another. Furthermore, antibodies 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 of one or more new strains in each year's influenza vaccine. Therefore, influenza vaccines are standardized to contain the hemagglutinins of influenza virus strains (ie, typically two type A and one type B), representing the influenza viruses likely to be circulating in the US in the upcoming winter.

Annual vaccination with the current vaccine is recommended because immunity during the year after vaccination declines, and because circulating strains of influenza virus change from year to year. (4)

Clinical Studies

Immunogenicity of Fluzone in Children 6 Months through 8 Years of Age

In a multi-center study conducted in the US, 68 children 6 months through 35 months of age given two 0.25 mL doses of Fluzone and 120 children 3 years through 8 years of age given two 0.5 mL doses of Fluzone were included in the per-protocol analysis set. The two doses (year 2006-2007 formulation) were administered 26 to 30 days apart. Females accounted for 42.6% of the participants in the 6 months through 35 months age group and 53.3% of the participants in the 3 years through 8 years age group. Most participants in the 6 months through 35 months and 3 years through 8 years age groups, respectively, were Caucasian (70.6% and 79.2%), followed by Hispanic (19.1% and 13.3%), and Black (7.4% and 4.2%).

The percentage of participants who received influenza vaccination during the previous influenza season was 54.4% for the 6 months through 35 months age group and 27.5% for the 3 years through 8 years age group. Table 9 shows seroconversion rates and the percentage of participants with an HI titer ≥ 1:40 one month following the second dose of Fluzone.

Table 9: Percentage (%) with an HI Titer ≥ 1:40 and Seroconversion Following the Second Vaccine Injection with Fluzone^a in Children 6 Months Through 35 Months and 3 Years Through 8 Years of Age

Immunogenicity of Fluzone and Fluzone Intradermal in Adults

Adults 18 through 64 years of age were randomized to receive Fluzone Intradermal or Fluzone (year 2008-2009 formulation) in a multi-center trial conducted in the US. The trial was open-label for administration route. For immunogenicity analyses, there were 2581 participants who received Fluzone Intradermal and 1287 participants who received Fluzone in the per protocol analysis set. There were fewer males than females (36.1% and 35.8% males in the Fluzone Intradermal and Fluzone groups, respectively). In the Fluzone Intradermal group, the mean age was 42.7 years (ranged from 18.1 through 65.0 years), and in the Fluzone group, the mean age was 42.6 years (ranged from 18.2 through 65.0 years). Most participants in the Fluzone Intradermal and Fluzone groups, respectively, were Caucasian (79.6% and 80.0%), followed by Hispanic (10.2% and 11.0%), and Black (7.7% and 6.3%). HI antibody geometric mean titers (GMTs) following Fluzone Intradermal were non-inferior to those following Fluzone for all three strains. (See Table 10) Seroconversion rates following Fluzone Intradermal were non-inferior to those following Fluzone for strains A (H1N1) and A (H3N2), but not for strain B. (See Table 11) At 28 days following vaccination with either Fluzone or Fluzone Intradermal, the percentages of subjects with a serum HI antibody titer of at least 1:40 ranged from 87% to 92%, depending on the influenza strain.

Table 10: Non-inferiority of Fluzone Intradermal Relative to Fluzone by HI Antibody GMTs at 28 Days Post Vaccination, Adults 18 through 64 Years of Age

Table 11: Non-inferiority of Fluzone Intradermal Relative to Fluzone by HI Antibody Seroconversion at 28 Days Post Vaccination, Adults 18 through 64 Years of Age

Immunogenicity of Fluzone in Adults and Geriatric Adults

In two observational studies, the immunogenicity of a single dose of Fluzone (year 1999-2000 and year 2000-2001 formulation, respectively) was evaluated in adults 19 through 59 years of age (median age: 38 years) and adults 61 through 86 years of age (median age: 72 years). The percentages of subjects with post-vaccination HI titers > 1:40 and a four-fold increase in titer from pre-vaccination to post-vaccination were analyzed. (See Table 12)

Table 12: Percentage of Subjects with HI Titer ≥ 1:40 and 4-Fold Increase in HI Titer Following Fluzone, Adults 19 through 59 Years of Age and 61 through 86 Years of Age

Immunogencity of Fluzone and Fluzone High-Dose in Geriatric Adults

Adults 65 years of age and older were randomized to receive either Fluzone High-Dose or Fluzone (year 2006-2007 formulation) in a multi-center, double-blind trial conducted in the US. For immunogenicity analyses, 2,576 participants were randomized to Fluzone High-Dose and 1,275 participants were randomized to Fluzone. Females accounted for 51.3% of participants in the Fluzone High-Dose group and 54.7% of participants in the Fluzone group. In both groups, the mean age was 72.9 years (ranged from 65 through 97 years in the Fluzone High-Dose group and 65 through 94 years in the Fluzone group); 35% of participants in the Fluzone High-Dose group and 36% of participants in the Fluzone group were 75 years of age or older. Most participants in the Fluzone High-Dose and Fluzone groups, respectively, were Caucasian (91.7% and 92.9%), followed by Hispanic (4.8% and 3.7%), and Black (2.7% and 2.7%).

The primary endpoints of the study were HI GMTs and seroconversion rates 28 days after vaccination. Pre-specified statistical superiority criteria required that the lower limit (LL) of the 2-sided 95% CI of the GMT ratio [Fluzone High-Dose/Fluzone] be greater than 1.50 for at least two of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated (LL > 0.67), and that the lower limit of the 2-sided 95% CI of the seroconversion rate difference [Fluzone High-Dose minus Fluzone] be greater than 10% for at least two of the strains, and if one strain failed, non-inferiority of that strain must be demonstrated (LL > -10%). As shown in Table 13, statistically superior HI GMTs and seroconversion rates after vaccination with Fluzone High-Dose compared to Fluzone were demonstrated for influenza A subtypes, A (H1N1) and A (H3N2), but not for influenza type B. For strain B, non-inferiority of Fluzone High-Dose compared to Fluzone was demonstrated for both the HI GMTs and seroconversion rates. There are no data demonstrating clinically relevant prevention of culture-confirmed influenza or its complications after vaccination with Fluzone High-Dose compared to Fluzone in individuals 65 years of age and older.

Table 13: Post-Vaccination HI Antibody GMTs and Seroconversion Rates and Analyses of Superiority of Fluzone High-Dose Relative to Fluzone, Adults 65 Years of Age and Older

REFERENCES

1. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barre´ syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med 1998;339(25):1797-802.

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, Ward-Gardner Al. The role of serum haemagglutintion-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb 1972;767-777.

4. Centers for Disease Control and Prevention. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(RR-8):1-68.

Last reviewed on RxList: 1/11/2012
This monograph has been modified to include the generic and brand name in many instances.