Antibodies against Plasmodium falciparum malaria at the molecular level

Abstract

Malaria is a vector-borne disease of global importance, with the vast majority of its life-threatening cases caused by infection with Plasmodium falciparum parasites. Repeated exposure to P. falciparum leads to naturally occurring immunity, but this is not sterilizing and is relatively short-lived. However, antibodies can protect from the disease, as has been shown by serum transfer studies in humans and in animal models. Recent advances in single-cell antibody cloning technologies have enabled the characterization of recombinant monoclonal antibodies against parasite antigens at the molecular level. This work has significantly advanced our understanding of how protective antibodies against P. falciparum are generated, what their molecular features are, their epitope specificity and binding modes, and the formation of memory B cell responses. Here we review these recent advances, with a particular emphasis on human antibody responses. We discuss how these discoveries have laid the foundation for the development of novel intervention strategies, as well as having conceptual implications beyond the malaria field.

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Fig. 1: Domain organization of Plasmodium falciparum circumsporozoite protein and its recognition by human monoclonal antibodies.
Fig. 2: Affinity maturation for homotypic antibody–antibody interactions has been observed in humans to optimize recognition of Plasmodium falciparum.
Fig. 3: Molecular basis of erythrocytic-stage inhibition of Plasmodium falciparum by monoclonal antibodies.
Fig. 4: Antibody diversification through gene insertions for the recognition of Plasmodium falciparum.
Fig. 5: Molecular basis of transmission-blocking antibodies against Plasmodium falciparum.

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Acknowledgements

The authors thank E. A. Levashina for discussions and critical reading of the manuscript. This Review was undertaken, in part, thanks to funding from the Canada Research Chairs program (to J.-P.J.).

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Glossary

Sterilizing immunity

An immune response that prevents the establishment of the infection or the development of erythrocytic-stage parasites.

Controlled human malaria infection

Deliberate infection of humans with Plasmodium parasites by either mosquito bite or injection of sporozoites or infected erythrocytes. This model is widely used to investigate the potency of drug and vaccine candidates.

Chemoprophylaxis

Drug-mediated attenuation of parasite development in the liver or blood to prevent malaria disease.

Circumsporozoite precipitation reaction

Antibody-mediated precipitation of circumsporozoite protein from the surface of Plasmodium sporozoites, which leads to parasite immobilization associated with impaired infectivity.

RTS,S/AS01

The first human PfCSP-based vaccine against the pre-erythrocytic stage of malaria.

Complementarity-determining region 3

(CDR3). A hypervariable region of membrane-bound and soluble B cell receptors that is involved in antigen binding.

Fab molecules

The antigen-binding fragments of immunoglobulin molecules.

Variant surface antigens

Proteins encoded by Plasmodium gene families in sub-telomeric regions; they have functions in virulence and immune evasion.

Activation-induced cytidine deaminase

(AID). An enzyme expressed in germinal centre B cells that has a crucial function in somatic hypermutation and class-switch recombination.

Structure-guided vaccine design

Rational engineering of vaccine immunogens based on structural analysis of potent antibodies and their target epitopes.

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Julien, JP., Wardemann, H. Antibodies against Plasmodium falciparum malaria at the molecular level. Nat Rev Immunol 19, 761–775 (2019). https://doi.org/10.1038/s41577-019-0209-5

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