The overarching goal of this proposal is to use a systems biology approach to define innate signatures that can predict vaccine efficacy and immunogenicity in young adults and the elderly. To achieve this goal we have initiated a highly collaborative effort to perform a detailed cellular and molecular characterization of human immune responses induced by three distinct vaccines: (i) the T-dependent inactivated trivalent influenza vaccine ( TIV ), (ii) the T-independent pneumococcal polysaccharide vaccine 23 ( PPV23 ) and (iii) the live attenuated varicella-zoster vaccine ( zoster). These three vaccines were selected for this study because influenza virus, pneumococcus and VZV, are of global public health importance and the cause of severe morbidity and mortality, especially in the elderly and other high-risk groups . In addition, all three of these vaccines are known to generate sub-optimal immune responses in a substantial proportion of elderly vaccines. Defining the innate signatures in these sub-optimal responders may provide insight into the defects that underlie poor vaccine efficacy and immunogenicity in the elderly. This information may form the basis for developing rational strategies to enhance vaccine efficacy in the aged population. The goal of Project #2 is to characterize the key adaptive immune responses for each vaccine in the young and elderly cohorts. These data will then be used by the Genomics and Computational Biology Core to identify the innate signatures (Project #1) that predict the various adaptive immune parameters that are measured in Project #2. The following specific aims are proposed to achieve our goals: Aim 1: To characterize the adaptive immune responses induced by TIV vaccination in the young and the elderly. Aim 2: To characterize the magnitude and quality of the B cell mediated adaptive immune responses to pneumococcal vaccination in the young and the elderly. Aim 3: To characterize the adaptive immune responses in the young and elderly after zoster vaccination.