Scientific Project 1: Immune Responses to Preerythocytic Malaria This project will comprehensively define human immune responses during the pre-erythrocytic stage of Plasmodium falciparum infection and vaccination with attenuated sporozoites which prevents infection and thus target this stage. It will identify immune signatures during the pre-erythrocytic, immunization and post vaccination periods in complementary vaccine trials that assess protection by controlled human malaria infection (CHMI). The primary endpoint is a correlation of vaccine-induced protection from infection, secondary endpoints are the effects of prior malaria exposure and differences in immunization protocols, vaccines and CHMI methods. The exploratory endpoints include the identification of signals that implicate immune processes that contribute to protection. The approach combines formal statistical methods, well-defined endpoints and system biology analyses. It systematically integrates high-dimensional with diverse immunological analyses to generate an expansive immunological view to identify and assess signals that are associated with protection. It aims to: 1. Identify immune responses during the pre-erythrocytic stages of infection. Virtually nothing is known about this stage the infection in the liver during which there is extensive parasite replication and synthesis of new antigens. We will identify signals of infection and of immunization with attenuated SPZs during this stage and compare variations among trials. 2. Determine immune response kinetics over the immunization period. We will identify the kinetics of innate and adaptive immunological signals during immunization with attenuated SPZs and identify the development of those that correlate with protection and how these differ among the trials. We will deduce molecular and cellular features from the signals that correlate with each variable to provide insight into immune processes that are associated with each endpoint. 3. Compare responses at and following of malaria challenge infection. We will identify signatures in samples from vaccinees prior to and following assessment by CHMI of protection from infection. We will compare immune signatures that are associated with each endpoint. The results from all of the aims will be used to guide the selection and testing of specific hypotheses about the mechanisms that underlay each of the endpoints. Overall, the comprehensive and integrated immunological and systems biology analyses will identify immune signatures during the critical stage of infection by and immune protection against a complex protozoan pathogen. It will generate and analyze pooled data from multiple complementary vaccine trials in order to identify correlates of protection from infection, how these are affected by variables among the trials. It will provide insight into multiple aspects of immune processes that are operative during infection and affected by vaccination.