A Novel Phagocytosis Assay Reveals the Association between Elevated Opsonic Phagocytosis Levels and an Increased Risk of Clinical Malaria in a Low-Malaria Transmission Area

The authors of studies in high-malaria transmission areas have associated the opsonic phagocytosis (OP) of merozoites with protection from clinical malaria; however, OP studies have not been conducted in low transmission areas. In the current study, blood samples were collected from 5,753 individuals in a Kenyan highland area of low, unstable transmission in 2007 and monitored for clinical malaria through 2017. In a nested case-control design, individuals who developed clinical malaria (cases, N = 317) were matched 1:1 by age and village with those who did not (controls, N = 317). A novel OP assay was developed, and the association of OP with the risk of clinical malaria and IgG responses to Plasmodium falciparum antigens in individuals <5 years old, 5-14 years old, and ≥15 years old was examined. Opsonic phagocytosis levels increased with age; however, the proportion of individuals who tested positive for an OP response was <50% until individuals were ≥15 years old. After adjustment for potential confounding factors, OP levels were associated with an increased risk of clinical malaria in individuals 5-14 years old (adjusted odds ratio: 3.32 [CI: 1.13-9.77]) and ≥15 years old (adjusted odds ratio: 4.85 [CI: 1.02-23.00]), but not in children <5 years old (adjusted odds ratio: 0.57 [CI: 0.20-1.64]). In this low-malaria transmission area, OP responses did not develop in most individuals until they were ≥15 years old, and OP levels in individuals ≥5 years old were associated with an increased risk of clinical malaria, potentially reflecting that OP levels are markers of malaria exposure, providing additional information beyond standard geographic and intervention-based risk markers.