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Potent protection against malaria can be induced by attenuated live-immunization withPlasmodium falciparum(Pf) sporozoites (SPZ). However, a better understanding of the critical processes involved in the establishment of protective immunity is needed. We explored the safety and vaccine efficacy of early chemo-attenuation of PfSPZ under atovaquone-proguanil (AP). AP caused early arrest ofP. bergheiliver stages. Despite the absence of replication, robust protection in mice correlated with parasite-specific effector-memory CD8+T-cell responses. In a phase I clinical trial a single dose of AP prevented Pf infections in the liver of adult, human subjects who received three doses of 5.12x104or 1.5x105PfSPZ by direct venous inoculation combined with oral AP. However, only 2 of 8 (25%) and 2 of 10 (20%), respectively, were protected against controlled human malaria infection (CHMI) 10 weeks after the last vaccine dose, despite levels of IgG antibodies to the Pf circumsporozoite protein (PfCSP) comparable to those achieved in fully protected volunteers after immunization with 5.12x104PfSPZ with chloroquine chemoprophylaxis active only against subsequent blood stages. We identify lower IgG recognition of the secreted liver stage-specific antigens LISP2 and LSA1 and the multi-stage antigen MSP5 as immune signatures of inferior vaccine efficacy compared to PfSPZ with chloroquine chemoprophylaxis. In conclusion, we show that immune signatures of liver stage antigens, but neither an established rodent malaria model nor concentrations of antibodies against the major surface protein of sporozoites, permit prediction of vaccine efficacy. Thus, this study provides a clear rationale for the development of live sporozoite vaccination protocols that boost exposure to Pf liver stage antigens.Significance StatementOur research demonstrates that attenuation of liver infection of high doses ofPlasmodium falciparumsporozoites by concomitant single-dose administration of atovaquone-proguanil is safe in humans. However, vaccine efficacy was modest when compared to an identical protocol using chloroquine that acts only on the subsequent blood infection. Immune signatures of secretedP. falciparumliver stage antigens, but neither an established rodent malaria model nor concentrations of sporozoite antibodies, permit prediction of vaccine efficacy.