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Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C') inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C' inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.

Original publication

DOI

10.1016/j.immuni.2015.02.012

Type

Journal article

Journal

Immunity

Publication Date

17/03/2015

Volume

42

Pages

580 - 590

Keywords

Adolescent, Animals, Antibodies, Protozoan, Antigens, Protozoan, Child, Child, Preschool, Complement C1q, Complement Fixation Tests, Complement Pathway, Classical, Erythrocytes, Female, Gene Expression, Host-Pathogen Interactions, Humans, Immunoglobulin G, Malaria Vaccines, Malaria, Falciparum, Male, Merozoite Surface Protein 1, Merozoites, Parasitemia, Plasmodium falciparum, Prospective Studies, Protozoan Proteins