FLUAD vs. FLUZONE HD Influenza Vaccine in Residents of Long Term Care

As the primary endpoint, this trial is be using pre- to post-vaccine changes in HAI titers to
compare seroconversion rates and post-vaccination HAI titers to calculate the ratio of the
geometric mean titers in the two treatment groups. HAI is an in vitro bioassay that
determines a subject's serum levels of anti-influenza antibodies. The FDA uses this as a
standard immunogenicity assay for licensure. The trial will follow guidelines set out in the
FDA guidance document discussing non-inferiority immunogenicity studies. As additional
methods to assess immunogenicity, an assessment of anti-NA by performing NA inhibition assays
(NAI) and SVN assays will be added. A recent trial supported the use of NAI and SVN assays as
a correlate for protection in a trial of geriatric subjects. A healthy human challenge model
showed that NAI is more predictive of protection and reduced disease than HAI

In the large HD vaccine clinical efficacy trial (n=31,989) one third of subjects also had
immunogenicity data that allowed looking for correlations of immune assays with protection.
Their conclusions were that HAI and other immune assays are potential correlates of influenza
vaccine protection in older adults, and that the protective thresholds for the HAI assay in
the elderly appear consistent with those previously described for younger adults, provided
the assay virus matches the circulating virus.

Significance Data compiled by CDC in 2011-2012 showed that there were 1,383,700 residents in
NHs. Also about 4,742,500 patients received services from home health agencies, and 1,244,500
patients received services from hospices, collectively accounting for much of the frailest in
the US. Overall, these provider sectors served over 8 million people annually (2013). This
study will focus on residents in NHs but the findings of this study are highly relevant to
persons frail enough to require such services in all of settings where the vast majority are
at least 65 years old and thus appropriate for Fluad or HD, influenza vaccines licensed for
this age group.

The SD influenza vaccine has diminished efficacy in the older population with the more
debilitated LTC residents being among the worst responders yet with the highest mortality.
Deaths due to pneumonia and influenza and chronic lung disease were 20 times higher among NH
residents compared to community residents. The current availability of two vaccines
specifically for the elderly that both appear to work better than SD vaccine begs the
question: is the newer and less-costly Fluad vaccine non-inferior or even superior to HD
vaccine? The proposed study aims to initially address non-inferiority using immunologic
endpoints as this is feasible in the clinical trial R01 grant structure and a critical first
step to obtain head-to-head data from the same trial, cohort and vaccine years. This proposed
study itself may provide direct guidance on vaccine usage or inform a future trial assessing
actual superiority should that be appropriate based on the results of this study.

HD vaccine is increasingly used by older Americans despite its greater cost over the SD
vaccine and no preferential recommendation by the Advisory Committee on Immunization
Practices (ACIP), the CDC committee responsible for making the vaccine recommendations for
the U.S. A finding of non-inferiority in the primary endpoint would provide a strong
rationale to consider using Fluad over HD that could result in some cost avoidance across
large long-term care system in the U.S. The trial is not powered for a superiority analysis
but in a non-inferiority trial if the findings are substantial enough they may show
superiority.

In the normal seasonal setting, influenza strains drift antigenically and therefore vary from
year to year. The CDC's prediction many months before the vaccination season sets the
composition for the next season's vaccine, but does not always correctly anticipate the exact
strain match that eventually actually circulates. There are Medicare claims data and modeling
in the NH population that there is a significant increase in death and hospitalization in bad
match over good match years particularly when A/H3N2 predominates. In those mismatched years
in particular, heterologous immunity or immunity to other non-exact match strains becomes
much more important if the vaccine is going to provide any benefit that season. Fluad is an
adjuvanted vaccine that has been shown to have a more broad-based or heterologous immunity
than SD vaccine that is not adjuvanted. HD is also not adjuvanted. Broad based immunity is
especially desirable for A/H3N2 immunity as that has had 4 different circulating strains in
the last 5 years while circulating A/H1N1 has been the same for 5 years; i.e., vaccine
mismatch is more likely with the A/H3N2 circulating strain. A/H3N2 is associated with the
majority of influenza hospitalizations and death among the elderly.

Inclusion Criteria:

- > 65 years old

- Able to obtain consent from subject or legally authorized representative (subject to
provide assent if cognitively/physically able to do so)

- Able to participate throughout the study period

Exclusion Criteria:

- Recent illness (within 30 days) severe enough to require hospitalization or
physician-directed outpatient pharmacotherapy

- Administration of immunomodulatory agents (e.g. oral corticosteroids except prednisone
< 10 mg daily, cyclosporine, and biologics (DMARDS) for Rheumatologic/Dermatologic
conditions) in the last 3 months

- Cancer requiring treatment in the past three years, except for non- melanoma skin
cancers or cancers that have clearly been cured or carry an excellent prognosis
including prostate cancer.

- Myocardial infarction, major heart surgery (i.e. valve replacement or bypass surgery),
stroke, deep vein thrombosis or pulmonary embolus in the past 4 months

- Allergies or history of significant adverse reactions to any component of influenza
vaccine including egg protein and latex or after a previous dose of any influenza
vaccine.

- History of Guillian-Barré Syndrome within 6 weeks of a prior influenza vaccine.