Abstract
Background: Individuals living in malaria-endemic regions develop immunity against severe malaria, but it is unclear whether immunity against pre-erythrocytic stages that blocks initiation of blood-stage infection after parasite inoculation develops following continuous natural exposure. Methods: We cleared schoolchildren living in an area (health district of Saponé, Burkina Faso) with highly endemic seasonal malaria of possible sub-patent infections and examined them weekly for incident infections by nested PCR. Plasma samples collected at enrolment were used to quantify antibodies to the pre-eryhrocytic-stage antigens circumsporozoite protein (CSP) and Liver stage antigen 1 (LSA-1). In vitro sporozoite gliding inhibition and hepatocyte invasion inhibition by naturally acquired antibodies were assessed using Plasmodium falciparum NF54 sporozoites. Associations between antibody responses, functional pre-erythrocytic immunity phenotypes and time to infection detected by 18S quantitative PCR were studied. Results: A total of 51 children were monitored. Anti-CSP antibody titres showed a positive association with sporozoite gliding motility inhibition (P<0.0001, Spearman's ρ=0.76). In vitro hepatocyte invasion was inhibited by naturally acquired antibodies (median inhibition, 19.4% [IQR 15.2-40.9%]), and there were positive correlations between invasion inhibition and gliding inhibition (P=0.005, Spearman's ρ=0.67) and between invasion inhibition and CSP-specific antibodies (P=0.002, Spearman's ρ=0.76). Survival analysis indicated longer time to infection in individuals displaying higher-than-median sporozoite gliding inhibition activity (P=0.01), although this association became non-significant after adjustment for blood-stage immunity (P = 0.06). Conclusions: In summary, functional antibodies against the pre-erythrocytic stages of malaria infection are acquired in children who are repeatedly exposed to Plasmodium parasites. This immune response does not prevent them from becoming infected during a malaria transmission season, but might delay the appearance of blood stage parasitaemia. Our approach could not fully separate the effects of pre-erythrocytic-specific and blood-stage-specific antibody-mediated immune responses in vivo; epidemiological studies powered and designed to address this important question should become a research priority.
Highlights
The most advanced malaria vaccine, RTS,S, induces immune responses that target P. falciparum circumsporozoite protein (CSP) and thereby the pre-erythrocytic stages of malaria[1]
All but one study participant had P. falciparum parasites detected by 18S qPCR during follow-up
There was a positive correlation between gliding and invasion inhibition (Figure S3A in Extended data[14], P=0.02, Spearman’s ρ=0.60), suggesting that in vitro gliding inhibition by naturally acquired antibodies might serve as a good surrogate for in vitro hepatocyte invasion inhibition
Summary
The most advanced malaria vaccine, RTS,S (trade name, Mosquirix), induces immune responses that target P. falciparum circumsporozoite protein (CSP) and thereby the pre-erythrocytic stages of malaria[1]. Vaccination with the attenuated sporozoite vaccine PfSPZ resulted in a protective efficacy of ~48%, as quantified by differences in time to first positive blood smears in malaria-experienced adults in Mali[6]. The results of this and other vaccine trials and the efficient immunisation of malaria-naive individuals with multiple infected mosquito bites while receiving chloroquine[7] contrast with the limited epidemiological evidence of naturally acquired functional immunity to Plasmodium pre-erythrocytic stages. The high incidence of blood-stage re-infection after effective anti-malarial treatment in adults living in malaria-endemic regions suggests that sterilizing immunity does not develop even after years of repeated infection[10,11].
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