Briana Santaniello
09/09/14
Journal Club #2
DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of High-Dose versus Standard-Dose Influenza
Vaccine in Older Adults. N Engl J Med 2014;371:635-45.
Funding/Conflicts of Interest: Sanofi Pasteur, the vaccine manufacturer, had primary responsibility for study
design, protocol development, study monitoring, data management, and statistical analyses. Nine of the 17
authors are Sanofi Pasteur employees; however primary investigators are not employed by Sanofi Pasteur.
Background: Influenza is a contagious respiratory virus which spreads by respiratory droplets and can result in
mild to severe illness, or worse—death.1 Those at increased risk for influenza-related complications include, but
are not limited to, the elderly and the immunocompromised.1 Vaccination remains the most effective
intervention in preventing influenza and related complications.1 The CDC reports flu vaccination was associated
with a 77% reduction in influenza-related hospitalizations among adults 50 years of age or older during the
2011-2012 flu season.2
Study Purpose, Objectives, Rationale: In general, the elderly appear to have a decreased antibody response
and protection from illness. DiazGranados et al hypothesized that administration of an influenza vaccine
containing a greater amount of hemagglutinin would result in an improved antibody response and thus, greater
protection from influenza and its associated complications. The primary objective of the study is “to compare
the clinical efficacy of Fluzone High-Dose to that of Fluzone in elderly adults, with respect to laboratoryconfirmed influenza caused by any influenza viral types/subtypes, associated with the occurrence of a protocoldefined influenza-like-illness.”3 The secondary objectives of the study were “to compare the clinical efficacy of
Fluzone High-Dose to that of Fluzone in elderly adults with respect to culture-confirmed influenza caused by:
1. any influenza viral types/subtypes, associated with the occurrence of a protocol-defined ILI,
2. viral types/subtypes antigenically similar to those contained in the respective annual vaccine
formulations, associated with the occurrence of a modified Centers for Disease Control and Prevention
(CDC)-defined ILI,
3. any influenza viral types/subtypes, associated with the occurrence of a modified CDC-defined ILI,
4. viral types/subtypes antigenically similar to those contained in the respective annual vaccine
formulations, associated with the occurrence of a respiratory illness,
5. any influenza viral types/subtypes, associated with the occurrence of a respiratory illness, and
6. with respect to laboratory-confirmed influenza caused by any influenza viral types/subtypes, associated
with the occurrence of a protocol-defined ILI.”3
Respiratory illness = “the occurrence of one or more of the following: sneezing, nasal congestion or
rhinorrhea, sore throat, cough, sputum production, wheezing, or difficulty breathing”3
Protocol-defined influenza-like illness (primary outcome definition) = “a respiratory illness with sore throat,
cough, sputum production, wheezing, or difficulty breathing, concurrent with one or more of the following:
temperature above 37.2°C, chills, tiredness, headaches, or myalgia”3
Modified CDC-defined influenza-like illness = “a respiratory illness with cough or sore throat, concurrent
with a temperature above 37.2°C”3
Trial Design: The study was a phase IIIb-IV, multicenter, randomized, double-blind, active-controlled trial in
which 31,989 participants were enrolled from 126 research centers in the U.S. and Canada to receive IIV3-HD
(15,991) or IIV3-SD (15,998) over two enrollment periods: September 6 – October 9, 2011 and October 9 –
October 21, 2012. Concealed allocation was achieved through “an interactive voice-response system that
centrally assigned participants on the basis of computer-generated block randomization.”3 Furthermore,
“participants, investigators, and the sponsor’s study staff remained unaware of the study assignments.”3
Participants underwent rerandomization if they participated in the first and second year of the study.
If patients developed any respiratory symptoms (as defined above), they were instructed to contact the study
site; they were also contacted twice weekly by the call center until April 30 of each year. Participants who met
the criteria for any respiratory illness had nasopharyngeal swabs collected within 5 days of the onset of illness.
Polymerase-chain-reaction (PCR) assays were performed on the samples and if positive, the assay was
compared with the strains contained within the vaccine to determine if the strains were antigenically similar.
Collection rates were 80% for protocol-defined influenza-like illnesses, 73.6% of modified CDC-defined
influenza-like illnesses, and 67.2% of respiratory illnesses. Furthermore, “in the IIV3-SD group,
nasopharyngeal swabs were collected within the protocol-specified time frame for 79.3% of protocol-defined
influenza-like illnesses, 73.7% of modified CDC-defined influenza-like illnesses, and 66.8% of respiratory
illnesses.”3
Participant Enrollment: Participants were included if they were at least 65 years of age on the day of
vaccination, able to attend all scheduled visits and would comply with all trial procedures, must not have had
moderate or severe acute illnesses, and informed consent form was dated and signed. Exclusion criteria
included history of Guillain-Barré syndrome, systemic hypersensitivity or life-threatening reaction to the study
vaccines or their components, influenza vaccination within 6 months prior to enrollment, thrombocytopenia,
bleeding disorder, or receipt of anticoagulants contraindicating intramuscular vaccination, dementia, any
cognitive condition, alcohol abuse, or drug addiction at a stage that could interfere with study compliance, or
participation in another interventional study within 4 weeks preceding enrollment, investigators or their
employees or immediate family members, and deprivation of freedom.3
Treatment Interventions: Participants were randomized to receive either the standard-dose vaccine (IIV3-SD,
Fluzone, Sanofi Pasteur, 15 µg of HA/strain) or the high-dose vaccine (IIV3-HD, Fluzone High-Dose, Sanofi
Pasteur, 60 µg of HA/strain).
Primary Outcome: Occurrences of culture- or polymerase chain reaction (PCR)-confirmed influenza caused
by any influenza viral types/subtypes in association with a protocol-defined influenza-like illness ≥ 14 days
post-vaccination.
Secondary Outcomes: Occurrences of culture-confirmed influenza caused by:
1. influenza viral types/subtypes that are antigenically similar to those contained in the vaccine
formulations, in association with a protocol-defined influenza-like illness,
2. any influenza viral types/subtypes, in association with a protocol-defined influenza-like illness,
3. influenza viral types/subtypes that are antigenically similar to those contained in the vaccine
formulations, in association with a modified CDC-defined influenza-like illness,
4. any influenza viral types/subtypes, in association with a modified CDC-defined influenza-like illness,
5. influenza viral types/subtypes that are antigenically similar to those contained in the vaccine
formulations, in association with a respiratory illness, and
6. any influenza viral types/subtypes, in association with a respiratory illness.
Statistical Analyses: To show superior efficacy (IIV3-HD vs. IIV3-SD), a sample size of 30,000 participants
was required to provide 80% power. There is an assumption of a relative vaccine efficacy of 30% and an
influenza incidence of 2% for the IIV3-HD group.3
Patient Demographics: Baseline characteristics include a mean age of 73.3 +/- 5.8 years, 57% female, 94.4%
white, 0.7% Asian, 4.2% Black, 0.6% Other, 67.2% had at least one prespecified chronic coexisting condition,
and 33.7% had at least two predisposed chronic coexisting conditions.3 These conditions include: CAD, AFib,
valvular heart disease, CHF, COPD, asthma, sickle cell disease, DM, hypothyroidism, CKD, chronic hepatitis,
cirrhosis, stroke, epilepsy, spinal cord injury, PD, cancer, long-term systemic corticosteroid therapy, other
potentially immunosuppressive therapy, and HIV/AIDS.3 Withdrawal rates were 834/15,991 for the IIV3-HD
group and 875/15,998 for the IIV3-SD group.
Power: After all dropouts had been accounted for, the total sample size was 30,467 and had 80% power.
Results for Primary Outcome: “228 participants in the IIV3-HD group (1.4%) and 301 participants in the
IIV3-SD group (1.9%) had laboratory confirmed influenza caused by any viral type or subtype associated with a
protocol-defined influenza-like illness (relative efficacy: 24.2%)”3
Results for Secondary Outcome: [see handout]
Safety and Tolerability: 8.3% in IIV3-HD group and 9.0% in IIV3-SD group had ≥ 1 serious adverse event;
0.5% of the participants in both the IIV3-HD and the IIV3-SD group died (unrelated to vaccination); 0.6%
IIV3-HD participants and 0.6% IIV3-SD participants discontinued the study due to serious adverse events
(unrelated to the study)
Author’s Conclusions/Limitations: Limitations include efficacy estimates with insufficient precision, a low
number of influenza viruses identified were similar to the vaccine, and exclusion of participants with moderate
or severe acute illnesses or unable to comply with study procedures. In conclusion, “IIV3-HD as compared with
IIV3-SD significantly improved protection against laboratory-confirmed influenza illness. It also showed that
IIV3-HD was associated with superior immune responses as compared with IIV3-SD.”3
Student’s Conclusions/Limitations: Although statistically significant, the findings do not appear to be
clinically significant. The assumption is that 2% of the IIV3-SD group would have influenza. A 1.4% incidence
vs. a 1.9% incidence in the IIV3-HD and IIV3-SD groups, respectively, does not appear to indicate that IIV3HD provides significant benefit over IIV3-SD. Furthermore, the fact that only 80% of the protocol-defined
influenza-like illnesses in the IIV3-HD group had nasopharyngeal swabs collected within the protocol-specified
time frame raises some question. Although this percentage is similar to that of the IIV3-SD group (79.3%),
there is uncertainly regarding the true incidence of influenza between the two vaccine groups. Hypothetically, t
is entirely possible that the 20% of uncollected IIV3-HD swabs had influenza, while the 20.7% of the
uncollected IIV3-SD swabs did not.
External Validity/Generalizability: Many retail chains suggest that pharmacists recommend IIV3-HD to
individuals over the age of 65 because of its proposed enhanced efficacy. With the results of the study,
pharmacists can now use this information to determine whether the IIV3-HD should be recommended over the
IIV3-SD.
Clinical Significance: With such a small improvement in the reduction in influenza incidence in the IIV3-HD
group compared to the IIV3-SD group, it does not appear that IIV3-HD provides enough clinically significant
benefit to justify its additional cost.
Areas of Further Research: It would be wise to complete a similar study which compares the efficacy of IIV3HD compared to IIV3-SD in other immunocompromised individuals (i.e. those with autoimmune disorders),
rather than only in older individuals. As the vaccine appears to provide statistically significant benefit to older
individuals, the vaccine may also extend some benefit to younger individuals, hopefully even a clinically
significant benefit.
References
1. Centers for Disease Control and Prevention. Key Facts about Influenza (Flu) & Flu Vaccine. CDC. 14
Aug 2014.
2. Centers for Disease Control and Prevention. Vaccine Effectiveness—How Well Does the Flu Vaccine
Work? CDC. 1 May 2014.
3. Diaz Granados CA, Dunning AJ, Kimmel M, et al. Efficacy of High-Dose versus Standard-Dose
Influenza Vaccine in Older Adults. N Engl J Med 2014;371:635-45.