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 participants.
(See REFERENCES 3 and 4.)
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 representing the influenza viruses likely to be
circulating in the US during the influenza season.
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.
Immunogenicity Of Fluzone High-Dose In Adults 65 Years Of Age And Older
Study 1 (NCT00391053) was a multi-center, double-blind pre-licensure trial conducted in the US in
which adults 65 years of age and older were randomized to receive either Fluzone High-Dose or
Fluzone (2006-2007 formulation). The study compared the safety and immunogenicity of Fluzone High-
Dose to those of Fluzone. For immunogenicity analyses, 2576 participants were randomized to Fluzone
High-Dose and 1275 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 White (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 3, 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
Table 3: Study 1 : 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
||Met Both Pre-defined Superiority
High - Dose
†Seroconversion: Paired samples with pre-vaccination HI titer <1:10 and post-vaccination (day 28)
titer ≥1:4 0 or a minimum 4 -fold increase for participants with pre-vaccination titer ≥1:10
‡Predefined superiority criterion for seroconversion: the lower limit of the two-sided 95% CI of the
difference of the seroconversion rates (Fluzone High-Dose minus Fluzone) is >10%. Predefined
superiority criterion for the GMT ratio: the lower limit of the 95% CI of the GMT ratio (Fluzone
High-Dose divided by Fluzone) is >1.5
§N is the number of vaccinated participants with available data for the immunologic endpoint listed
Efficacy Of Fluzone High-Dose In Adults 65 Years Of Age And Older
Study 2 (NCT01427309) was a multi-center, double-blind post-licensure efficacy trial conducted in the
US and Canada in which adults 65 years of age and older were randomized (1:1) to receive either
Fluzone High-Dose or Fluzone. The study was conducted over two influenza seasons (2011-2012 and
2012-2013); 53% of participants enrolled in the first year of the study were re-enrolled and rerandomized
in the second year. The per-protocol analysis set for efficacy assessments included 15,892
Fluzone High-Dose recipients and 15,911 Fluzone recipients. The majority (67%) of participants in the
per-protocol analysis set for efficacy had one or more high-risk chronic comorbid conditions.
In the per-protocol analysis set, females accounted for 57.2% of participants in the Fluzone High-Dose
group and 56.1% of participants in the Fluzone group. In both groups, the median age was 72.2 years
(range 65 through 100 years). Overall, most participants in the study were White (95%); approximately
4% of study participants were Black, and approximately 6% reported Hispanic ethnicity.
The primary endpoint of the study was the occurrence of laboratory-confirmed influenza (as determined
by culture or polymerase chain reaction) caused by any influenza viral type/subtype in association with
influenza-like illness (ILI), defined as the occurrence of at least one of the following respiratory
symptoms: sore throat, cough, sputum production, wheezing, or difficulty breathing; concurrent with at
least one of the following systemic signs or symptoms: temperature >99.0°F, chills, tiredness,
headaches or myalgia. Participants were monitored for the occurrence of a respiratory illness by both
active and passive surveillance, starting 2 weeks post-vaccination for approximately 7 months. After an
episode of respiratory illness, nasopharyngeal swab samples were collected for analysis; attack rates
and vaccine efficacy were calculated (see Table 4).
Table 4: Study 2 : Relative Efficacy Against Laboratory-Confirmed
Influenza Regardless of Similarity to the Vaccine Components ,
Associated with Influenza-Like Illness , Adults 65 Years of Age and
% (95% CI)
||24.2 (9.7; 36.5)Þ
| Influenza A
||23.6 (7.4; 37.1)
| A (H1N1)
||11.0 (-159.9; 70.1)
| A (H3N2)
||22.9 (5.4; 37.2)
| Influenza Bß
||27.4 (-13.1; 53.8)
†Laboratory-confirmed: culture- or polymerase-chain-reaction-confirmed
‡Occurrence of at least one of the following respiratory symptoms: sore throat,
cough, sputum production, wheezing, or difficulty breathing; concurrent with at least
one of the following systemic signs or symptoms: temperature >99.0°F, chills,
tiredness, headaches or myalgia
§N is the number of vaccinated participants in the per-protocol analysis set for
¶n is the number of participants with protocol-defined influenza-like illness with
ÞThe pre-specified statistical superiority criterion for the primary endpoint (lower limit
of the 2-sided 95% CI of the vaccine efficacy of Fluzone High-Dose relative to
Fluzone > 9.1%) was met.
ßIn the first year of the study the influenza B component of the vaccine and the
majority of influenza B cases were of the Victoria lineage; in the second year the
influenza B component of the vaccine and the majority of influenza B cases were of
the Yamagata lineage
A secondary endpoint of the study was the occurrence of culture-confirmed influenza caused by viral
types/subtypes antigenically similar to those contained in the respective annual vaccine formulations in
association with a modified CDC-defined ILI, defined as the occurrence of a temperature > 99.0°F (>
37.2°C) with cough or sore throat. The efficacy of Fluzone High-Dose relative to Fluzone for this
endpo int was 51.1% (95% CI: 16.8; 72.0).
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, Ward-Gardner A. The role of serum haemagglutinationinhibiting
antibody in protection against challenge infection with influenza A2 and B viruses. J
Hyg Camb 1972;70:767-777.