ABSTRACT Systems vaccinology approaches are defining molecular signatures that can predict vaccine induced immune responses in humans. These studies have mostly used healthy adults and two important vaccine target populations, children and the elderly, have not been examined in detail. In this proposal we extend the systems vaccinology approach to these two target populations at the extremes of age; infants (12-15 months old) and the elderly over 70 years. Herpes zoster (shingles), which is caused by VZV, affects several million people/year globally and is a significant public health concern for the elderly. Zostavax®, the currently licensed live VZV vaccine against zoster, has limited efficacy in subjects >70yrs old. An investigational recombinant glycoprotein E subunit vaccine (gE vaccine) has shown promising results in phase I trials but no comparative studies have been done with these two vaccines. In Aim 1 we will undertake a systems level analysis of innate responses induced by the live Zostavax® versus gE vaccine in the elderly, and identify molecular correlates of adaptive immunity (Project 2). These studies will provide insight into the molecular networks driving immunity induced by these zoster vaccines. VZV also causes chickenpox in children and the live Varivax® vaccine is highly effective in preventing chickenpox yet there is a paucity of knowledge about the nature of innate and adaptive immunity to vaccination in the pediatric population. In Aim 2 we will conduct a systems analysis of innate responses induced by Varivax® in infants and children, and define signature that predict adaptive immunity (Project 2). These studies in Aims 1 and 2 should provide new insights into understanding the immune response to the same vaccine at the two extremes of age. Finally, in Aim 3, we will use systems vaccinology approaches to probe the immune response of transplant recipients to vaccination against pneumococcal diseases. Our proposed studies with this immunocompromised population that is at high risk against invasive pneumococcal disease could provide new guidelines for pneumococcal vaccination in transplant recipients. These studies will yield important new insights into the mechanisms underpinning vaccine-induced immunity in these special target populations, and help define molecular signatures that predict immunogenicity.