T-cell Response-Flu Risk in Older Adults

This study will increase the understanding of how age, congestive heart failure (CHF) or a
prior hospitalization for an influenza-related acute coronary event affect the immune
response to influenza vaccination. By elucidating the defects in the immune response to
influenza vaccination that are associated with the subsequent influenza illness, these
methods can be used to screen subsets of older adults to establish the risk profile related
to influenza in that population, to target these defects for future vaccine development and
to use these methods as surrogates of protection to screen potential vaccines prior to
conducting large scale clinical trials to establish clinical efficacy. The primary objective
is to show that granzyme B (Grz B) levels in influenza virus-stimulated peripheral blood
mononuclear cell cultures are lower in older adults who receive inactivated influenza vaccine
(IIV) and subsequently develop influenza illness compared to those who do not. Secondary
objectives are to: (1) establish a cut-off value for Grz B as a marker of increased risk for
influenza illness; (2) show that interferon-gamma (IFN-gamma) levels are lower and
interleukin-10 (IL-10) levels are higher in influenza virus-stimulated peripheral blood
mononuclear cell cultures from vaccinated older adults who subsequently develop influenza
illness compared to those who do not; (3) determine the effect of macrophage migration
inhibitory facator (MIF) on T-cell responses to influenza vaccination; (4) determine the
association between CHF and ischemic heart disease (IHD) including acute coronary syndromes
and the immune response to influenza vaccination; (5) determine the effect of functional
status measured by the Six-Minute Walk Test (SMWT) on immune responsiveness to influenza
vaccination; (6) determine the effect of medications with anti-inflammatory effects including
angiotensin converting enzyme inhibitors (ACEI) and cholesterol-lowering drugs (statins) on
immune responsiveness to influenza vaccination; (7) evaluate the effect of the age-related
decline in the expression of the costimulatory molecule, CD28, on cytotoxic T-lymphocytes, on
the Grz B response to influenza vaccination; (8) study the potential role of
activation-induced cell death (AICD) on the T helper type 1 (Th1: IFN-gamma) versus T helper
type 2 (Th2: IL-10) response to influenza vaccination; (9) determine in vitro whether or not
co-stimulatory molecules such as 4-1BB ligand or CD70 can be used to augment the cytokine,
Grz B or CTL responses to influenza vaccines in older adults; (10) determine in vitro whether
or not heat shock proteins (HSP) can be used to augment the cytokine and/or Grz B response to
influenza vaccination in older adults; (11) determine in vitro whether or not heat shock
proteins (HSP) can be used to augment the cytokine and/or Grz B response to influenza
vaccination in older adults who develop influenza illness in spite of influenza vaccination;
and (12) determine in vitro whether or not heat shock proteins (HSP) increase the frequency,
Grz B content or proportion of influenza virus-specific CTL expressing CD28 in vaccinated in
older adults. The study group will consist of 150 adults, age 60 years and older,
characterized according to age, presence of CHF or IHD, or (to be identified in the prior
influenza season) an admission with an acute coronary syndrome or exacerbation of CHF. All
subjects will be vaccinated in the fall of each year with the current preparation of
trivalent, split-virus influenza vaccine. Serum antibody titers, serum cytokine levels, ex
vivo levels of IFN-gamma and IL-10, and ex vivo and in vitro levels of Grz B in
influenza-stimulated peripheral blood mononuclear cell at pre-vaccination and
post-vaccination (4, 10 and 16-20 weeks) time points will be compared in subjects who do and
do not get influenza illness. The peak as well as the duration of response to vaccination for
each of the immunologic measures will be determined.

Inclusion Criteria:

- Willing to be vaccinated with the current influenza vaccine.

- Healthy young adults are 20-40 years and have no underlying chronic diseases.

- 'Healthy' older adult participants are age 60 and older who may have underlying
chronic diseases but no diagnosis of CHF, advanced kidney disease or diabetes
requiring insulin.

- High-risk older adults with cardiovascular disease are age 60 years and older and have
a diagnosis of CHF, or IHD including ACS in the previous winter season.

Exclusion Criteria:

- Allergic reactions to eggs or preservatives such as those contained in contact lens
solutions.

- A previous significant reaction to vaccination or if they refuse to receive influenza
vaccination.

- Known immunosuppressive disorders or medications (including oral prednisone in doses
>10 mg daily) or have not received influenza vaccination in the past.

- Subjects who report respiratory illness within the two-week period prior to
vaccination. Subjects reporting respiratory symptoms at the first study visit are
re-scheduled to a time when they have not had a respiratory illness (at least two
symptoms of cough, runny nose, malaise and fever) within the two-week period prior to
vaccination.

- Cardiovascular diseases due to intravenous drug abuse, myocarditis or congenital
abnormalities

- Any condition that in the opinion of the investigator would interfere with the
interpretation or the evaluation of the vaccine