Human Antibodies Fix Complement to Inhibit Plasmodium falciparum Invasion of Erythrocytes and Are Associated with Protection against Malaria

Abstract

SummaryAntibodies 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.

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

“…In agreement with preclinical studies, these data confirmed the vaccine-induced antibodies in humans were strain transcending, showing activity against all tested parasites. Notably, addition of human complement did not increase levels of GIA, as reported for some merozoite surface proteins (65). This is perhaps not surprising, given that antibodies only have a very short window of opportunity to bind RH5 following its release from the rhoptries, likely leading to time constraints on complement recruitment.…”

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

“…Hodder et al , 2001; Miura et al , 2009; Reiling et al , 2012; Schwartz et al , 2012). In a new study, however, Boyle et al (2015) demonstrated that acquired invasion‐inhibitory antibodies act through binding of C1q and activation of the classical complement pathway rather than by functionally inhibiting invasion. Without active complement, the majority of antibodies against merozoite surface proteins like MSP1 were not effective.…”

Dichotomous miR expression and immune responses following primary blood-stage malaria

“…A more comprehensive investigation of the antibody response showed that high-miR responders had significantly increased IgG1, IgG3, and IgM anti-merozoite responses compared with low responders. These observations are important, as IgG1 and IgG3 are cytophilic antibody subclasses that function against merozoite antigens by fixing complement to the merozoite surface, inhibiting invasion (25) and enhancing opsonic phagocytosis (26). Moreover, cytophilic subclass antibodies (IgG1 and IgG3) against MSP1 and MSP2 have been associated with protection from malaria in longitudinal cohort studies in children (23,24,27).…”