Abstract
Background: Individuals living in malaria-endemic regions develop naturally acquired immunity against severe malarial disease, but it is unclear whether immunity that affects the establishment of infections develops following continuous natural exposure. Methods: We cleared schoolchildren in Burkina Faso of possible sub-patent infections and examined them weekly for incident infections by PCR. Plasma samples collected at enrolment were used to quantify antibodies to the pre-eryhrocytic-stage antigens circumsporozoite protein (CSP) and liver stage antigen. Sporozoite gliding inhibition by naturally acquired antibodies was assessed using Plasmodium falciparum NF54 sporozoites; hepatocyte invasion was assessed using the human HC-04 hepatoma cell line and NF54 sporozoites. The associations between these functional pre-erythrocytic immunity phenotypes and time to PCR-detected infection were studied. Results: A total of 51 children were monitored; the median time to first detection of infection by PCR or development of clinical symptoms was 28 days. Anti-CSP antibody titres showed a strong 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 invasion inhibition, 19.4% [IQR 15.2-40.9%]), and there was a positive correlation between gliding and invasion inhibition (P=0.02, Spearman's ρ=0.60). Survival analysis indicated longer time to infection in individuals displaying higher-than-median sporozoite gliding inhibition activity (P=0.01). 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 and consequently needs to be considered in the evaluation of malaria vaccines.
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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