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Immunoepidemiological studies typically reveal slow, age-dependent acquisition of immune responses against  Plasmodium falciparum  sporozoites. Naturally acquired immunity against preerythrocytic stages is considered inadequate to confer protection against clinical malaria. To explore previously unrecognized antisporozoite responses, we measured serum levels of naturally acquired antibodies to whole  Plasmodium falciparum  sporozoites ( Pf spz) and the immunodominant (NANP) 5  repeats of the major sporozoite surface protein, circumsporozoite protein, in a well-characterized Kenyan cohort. Sera were sampled at the start of the malaria transmission season, and all subjects were prospectively monitored for uncomplicated clinical malaria in the ensuing 6 months. We used Kaplan–Meier analysis and multivariable regression to investigate the association of antisporozoite immunity with incidence of clinical malaria. Although naturally acquired humoral responses against  Pf spz and (NANP) 5  were strongly correlated ( p  < 0.0001), 37% of  Pf spz responders did not recognize (NANP) 5 . The prevalence and magnitude of antisporozoite responses increased with age, although some high  Pf spz responders were identified among children. Survival analysis revealed a reduced risk of and increased time to first or only episode of clinical malaria among  Pf spz or (NANP) 5  responders carrying microscopically detectable  Plasmodium falciparum  ( Pf ) parasitemia at the start of the transmission season ( p  < 0.03). Our Cox regression interaction models indicated a potentially protective interaction between high anti- Pf spz ( p  = 0.002) or anti-(NANP) 5  ( p  = 0.001) antibody levels and microscopically detectable  Pf  parasitemia on the risk of subsequent clinical malaria. Our findings indicate that robust antisporozoite immune responses can be naturally acquired already at an early age. A potentially protective role of high levels of anti- Pf spz antibodies against clinical episodes of uncomplicated malaria was detected, suggesting that antibody-mediated preerythrocytic immunity might indeed contribute to protection in nature.

High Sporozoite Antibody Titers in Conjunction with Microscopically Detectable Blood Infection Display Signatures of Protection from Clinical Malaria