The goal of this proposal is to understand how a successful vaccine induces long-term immunologicalmemory in humans. To achieve this goal we propose to conduct a detailed cellular and molecularcharacterization of human immune responses induced by the yellow fever virus (YFV) vaccine. This is oneof our most efficacious vaccines and induces long-term immunity that lasts for decades. Also, since YFV-17D is a live attenuated vaccine and most of the U.S. population is not exposed to YFV, this provides aunique opportunity to analyze antiviral responses in humans during the course of a primary infection andthen to monitor the generation and maintenance of immune memory after resolution of the infection. One ofthe potential benefits of understanding how a successful vaccine induces long-term memory is that thisknowledge can be applied to improving other less effective vaccines. Such a comparison could define thesignatures of a 'good' versus 'bad' vaccine and provide a rational basis for improving vaccine efficacy. Toaddress this issue, we will examine human immune responses induced by the anthrax vaccine. We havechosen to study the anthrax vaccine because of the obvious importance of anthrax in biodefense-relatedresearch and also because there is clearly a need for a better anthrax vaccine. However, prior to designingstrategies for improving the anthrax vaccine, it is first essential to better characterize the magnitude andquality of the immune responses induced in humans by the currently licensed anthrax vaccine.
The specificaims of this proposal are as follows: 1. To determine if there is an early global sensitization of na'fve T and Bcells after immunization and to see if this correlates with the magnitude and duration of the adaptive immuneresponse. 2. To characterize the primary and memory T cell responses to YFV and anthrax vaccine. 3. Todefine the molecular and functional profile of memory T cell differentiation in vivo following an acute viralinfection and to examine how the strength and duration of T cell stimulation effects memory differentiation.4. To examine bystander effects on memory T cells during viral infection in humans. 5. To understand themechanisms of long-term serological memory and to define the gene expression profiles of memory B cells.
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