Abstract
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 (Pfspz) 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 Pfspz and (NANP)5 were strongly correlated (p < 0.0001), 37% of Pfspz responders did not recognize (NANP)5. The prevalence and magnitude of antisporozoite responses increased with age, although some high Pfspz responders were identified among children. Survival analysis revealed a reduced risk of and increased time to first or only episode of clinical malaria among Pfspz 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-Pfspz (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-Pfspz antibodies against clinical episodes of uncomplicated malaria was detected, suggesting that antibody-mediated preerythrocytic immunity might indeed contribute to protection in nature.
Highlights
IntroductionAn infected mosquito typically injects fewer than 40 motile sporozoites into the human skin [2]
Malaria transmission by Plasmodium-infected Anopheles mosquitoes results in at least 200 million malaria cases every year, and the majority of disease burden is caused by Plasmodium falciparum (Pf) infections in children [1].During a blood meal, an infected mosquito typically injects fewer than 40 motile sporozoites into the human skin [2]
Asymptomatic Pf blood stage infection at the beginning of the malaria transmission season was detected in 37% of individuals, this proportion was higher in younger age groups (3–15 years) (Table S1 in Supplementary Material)
Summary
An infected mosquito typically injects fewer than 40 motile sporozoites into the human skin [2]. When experimentally inoculated in repeated high doses, arrested, but metabolically active, Plasmodium sporozoites are able to elicit protective and often lasting and sterile immune responses against homologous challenge in humans [3,4,5]. Because the preerythrocytic phase of the life cycle is clinically silent, humans can be inoculated with high doses of sporozoites, providing a tantalizing rationale for preerythrocytic malaria vaccine approaches [6]. Plasmodium sporozoites are considered immunologically silent in natural infections, because they are mostly inoculated in small numbers and are exposed to the immune system only for a brief period [7, 8]
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