There is a need to increase protection against influenza conveyed to elderly persons by inactivated influenza virus vaccines. Serum antibody titer is the primary surrogate marker for immunity to influenza after vaccination; and increasing the antigen dose has been shown to increase the serum antibody response in vaccinated persons, including the elderly. However it is not known how the remainder of the immune system responds to the higher dose of influenza antigen. This study is linked to DMID protocols 04-100 and 05-0055. This study will be conducted as a substudy of DMID 04-100 at the University of Maryland, Baltimore. Subjects ages 65 years and older, who meet the entry criteria for the primary study, will be approached for participation in an immunology substudy of volunteers who receive a single intramuscular injection of either the high-dose or standard-dose of licensed 2004-2005 trivalent inactivated influenza vaccine. A minimum of 30 elderly subjects (with the possibility of up to 60 elderly subjects) will be enrolled for the substudy. The substudy will require an extra 100 ml (total blood draw of 120 ml) of blood drawn from the same 20 ml venipuncture obtained for hemagglutination inhibition assay (HAI) titers (as per the primary study) on days 0 and 28. To minimize adverse side effects, the additional 100 ml of blood required for the substudy will be obtained from the same venipuncture site from which the 20 ml blood will be obtained for HAI titers (i.e., if blood collection stops after the 20 ml for HAI are drawn, the researchers will not attempt to obtain additional blood from a separate venipuncture site). Subjects' blood will be evaluated for key humoral and cell-mediated immunity (CMI) responses to better understand the mechanisms underlying the predicted suboptimal immune responses to one or more of the three influenza vaccine antigens observed in the elderly. With regard to specific study objectives, blood samples will be submitted for the following analysis: (1) measurement of serum anti-HA (hemagglutinin) IgG and IgA antibodies by ELISA; (2) IgG antibody subclasses; (3) IgG and IgA avidity, (4) virus neutralizing functional assay; and (5) HAI antibody titer. Peripheral blood mononuclear cells (PBMC) isolated from these subjects will be evaluated for the following: (1) "central" and "effector" memory T cell responses, including their proliferative responses and cytokine production profiles by flow cytometry; (2) IFN-gamma production by ELISPOT, following specific antigenic stimulation; (3) measurement ex vivo of the frequency of circulating influenza-specific T cells by using commercially available MHC/tetramers and/or MHC/pentamers and flow cytometry; and (4) role of regulatory T cells in the modulation of influenza responses in the elderly. Studies for measurement ex vivo of the frequency of circulating influenza-specific T cells (by using commercially available MHC/tetramers and/or MHC/pentamers and flow cytometry) will concentrate on IFN-gamma, a cytokine shown by many investigators to play a central role in the host immune response to influenza antigens. If promising results are observed, other cytokines (e.g., IL-12, TNF-alpha) might also be evaluated in future investigations if sufficient cells and resources are available. Major factors involved in the decision to concentrate these studies on IFN-gamma include the need to remain focus in a defined set of scientific questions and the fact that we will only have access to a limited number of peripheral blood mononuclear cells (PBMCs) that might preclude the study of additional cytokines.