The development of effective interventions against malaria and other chronic infectious diseases is impeded by a lack of understanding of host-pathogen interactions and the mechanisms and antigenic targets underlying protective immunity. The fundamental premise of this proposal is that integrated and unbiased systems-level approaches provide an excellent framework to develop a comprehensive understanding of immune responses and identify key molecules/pathways that can be targeted for therapeutic intervention or for immunodiagnostics. Taking advantage of unique human experimental infection models and field studies, this research encompasses: (i) antigen discovery; (ii) host-pathogen immunity; (iii) vaccine engineering; and (iv) biomarker discovery. It will develop a pipeline of parasite antigens and immunomodulatory molecules that can be transitioned towards clinical development and testing, as well as identify biomarkers of disease risk that can be used for population based screening to define at-risk individuals for targeted intervention.