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BMC Medicine
Published in: BMC Medicine 1/2018

Open Access 01-12-2018 | Research article

Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children

Authors: Liriye Kurtovic, Marije C. Behet, Gaoqian Feng, Linda Reiling, Kiprotich Chelimo, Arlene E. Dent, Ivo Mueller, James W. Kazura, Robert W. Sauerwein, Freya J. I. Fowkes, James G. Beeson

Published in: BMC Medicine | Issue 1/2018

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Abstract

Background

Antibodies targeting Plasmodium falciparum sporozoites play a key role in human immunity to malaria. However, antibody mechanisms that neutralize sporozoites are poorly understood. This has been a major constraint in developing highly efficacious vaccines, as we lack strong correlates of protective immunity.

Methods

We quantified the ability of human antibodies from malaria-exposed populations to interact with human complement, examined the functional effects of complement activity against P. falciparum sporozoites in vitro, and identified targets of functional antibodies. In children and adults from malaria-endemic regions, we determined the acquisition of complement-fixing antibodies to sporozoites and their relationship with antibody isotypes and subclasses. We also investigated associations with protective immunity in a longitudinal cohort of children (n = 206) residing in a malaria-endemic region.

Results

We found that antibodies to the major sporozoite surface antigen, circumsporozoite protein (CSP), were predominately IgG1, IgG3, and IgM, and could interact with complement through recruitment of C1q and activation of the classical pathway. The central repeat region of CSP, included in leading vaccines, was a key target of complement-fixing antibodies. We show that antibodies activate human complement on P. falciparum sporozoites, which consequently inhibited hepatocyte cell traversal that is essential for establishing liver-stage infection, and led to sporozoite death in vitro. The natural acquisition of complement-fixing antibodies in malaria-exposed populations was age-dependent, and was acquired more slowly to sporozoite antigens than to merozoite antigens. In a longitudinal cohort of children, high levels of complement-fixing antibodies were significantly associated with protection against clinical malaria.

Conclusions

These novel findings point to complement activation by antibodies as an important mechanism of anti-sporozoite human immunity, thereby enabling new strategies for developing highly efficacious malaria vaccines. We also present evidence that complement-fixing antibodies may be a valuable correlate of protective immunity in humans.
Appendix
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Metadata
Title
Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children
Authors
Liriye Kurtovic
Marije C. Behet
Gaoqian Feng
Linda Reiling
Kiprotich Chelimo
Arlene E. Dent
Ivo Mueller
James W. Kazura
Robert W. Sauerwein
Freya J. I. Fowkes
James G. Beeson
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2018
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-018-1054-2

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