Understanding immune mechanisms that mediate malaria protection is critical for improving vaccine development. Vaccination with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) induces high level of sterilizing immunity against malaria and serves as a valuable tool for the study of protective mechanisms. To identify vaccine-induced and protection-associated responses during malarial infection, we performed transcriptome profiling of whole blood and in-depth cellular profiling of PBMCs from volunteers who received either PfRAS or noninfectious mosquito bites, followed by controlled human malaria infection (CHMI) challenge. In-depth single-cell profiling of cell subsets that respond to CHMI in mock-vaccinated individuals showed a predominantly inflammatory transcriptome response. Whole blood transcriptome analysis revealed that gene sets associated with type I and II interferon and NK cell responses were increased in prior to CHMI while T and B cell signatures were decreased as early as one day following CHMI in protected vaccinees. In contrast, non-protected vaccinees and mock-vaccinated individuals exhibited shared transcriptome changes after CHMI characterized by decreased innate cell signatures and inflammatory responses. Additionally, immunophenotyping data showed different induction profiles of vδ2+ γδ T cells, CD56+ CD8+ T effector memory (Tem) cells, and non-classical monocytes between protected vaccinees and individuals developing blood-stage parasitemia, following treatment and resolution of infection. Our data provide key insights in understanding immune mechanistic pathways of PfRAS-induced protection and infective CHMI. We demonstrate that vaccine-induced immune response is heterogenous between protected and non-protected vaccinees and that inducted-malaria protection by PfRAS is associated with early and rapid changes in interferon, NK cell and adaptive immune responses. Trial Registration: ClinicalTrials.gov NCT01994525. Author summary: Malaria poses a significant global health threat, causing over half a million deaths annually. Effective vaccines are critically needed to prevent malaria disease. Our incomplete understanding of immune mechanisms that mediate malaria protection is hampering the development of effective vaccines. Irradiated sporozoite vaccines can induce highly sterilizing protection against malaria and are a valuable tool for the analysis of immune protection. Here, we aimed to characterize correlates of immune protection in individuals vaccinated with a suboptimal dose of irradiated sporozoite and subsequently challenged with live malaria parasite. Blood samples were taken before and after malaria challenge, and gene expression and cell type profiles were measured. We observed that the trajectories of immune response after malaria challenge is highly distinct between protected and non-protected vaccinees. We observed early perturbations in interferon, NK cell, and adaptive immune responses in protected vaccinees whereas inflammatory and innate cell response were unique to non-protected vaccinees. We also observed that the immune profile after malaria challenge was distinctly similar between non-protected vaccinees and mock-vaccinated individuals. Our study sheds light on the dynamics of vaccine-induced immune responses that are associated with protection from malaria after CHMI. [ABSTRACT FROM AUTHOR]