An understanding of the mechanisms mediating protective immunity against
malaria in humans is currently lacking, but critically important to advance the development of highly efficacious
vaccines.
Antibodies play a key role in acquired immunity, but the functional basis for their protective effect remains unclear. Furthermore, there is a strong need for immune correlates of protection against
malaria to guide
vaccine development.
METHODS: Using a validated assay to measure opsonic phagocytosis of Plasmodium falciparum merozoites, we investigated the potential role of this functional activity in human immunity against clinical episodes of
malaria in two independent cohorts (n = 109 and n = 287) experiencing differing levels of
malaria transmission and evaluated its potential as a correlate of protection.
RESULTS:
Antibodies promoting opsonic phagocytosis of merozoites were cytophilic
immunoglobulins (
IgG1 and
IgG3), induced monocyte activation and production of pro-inflammatory
cytokines, and were directed against major merozoite
surface proteins (MSPs). Consistent with protective immunity in humans, opsonizing
antibodies were acquired with increasing age and
malaria exposure, were boosted on
re-infection, and levels were related to
malaria transmission intensity. Opsonic phagocytosis was strongly associated with a reduced risk of clinical
malaria in longitudinal studies in children with current or recent
infections. In contrast,
antibodies to the merozoite surface in standard immunoassays, or growth-inhibitory
antibodies, were not significantly associated with protection. In multivariate analyses including several antibody responses, opsonic phagocytosis remained significantly associated with protection against
malaria, highlighting its potential as a correlate of immunity. Furthermore, we demonstrate that human
antibodies against MSP2 and MSP3 that are strongly associated with protection in this population are effective in opsonic phagocytosis of merozoites, providing a functional link between these
antigen-specific responses and protection for the first time.
CONCLUSIONS: Opsonic phagocytosis of merozoites appears to be an important mechanism contributing to protective immunity in humans. The opsonic phagocytosis assay appears to be a strong correlate of protection against
malaria, a valuable
biomarker of immunity, and provides a much-needed new tool for assessing responses to blood-stage
malaria vaccines and measuring immunity in populations.