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.