Antibody correlates of risk of clinical malaria in an area of low and unstable malaria transmission in western Kenya

Background Defining antibody correlates of protection against clinical malaria in areas of low and unstable transmission is challenging because of limited malaria cases in these areas. Additionally, clinical malaria affects both adults and children in areas of low and unstable transmission, but it is unclear whether antibody correlates of protection against malaria differ with age. Methods Blood samples were obtained from 5753 individuals in Kenyan highland area with low and seasonal malaria transmission in 2007 and recorded episodes of clinical malaria in this population from 2007 to 2017. Using a nested case-control study design, participants who developed clinical malaria (cases) were matched by age and village to those who did not (controls). Immunoglobulin (Ig)G, IgG1, IgG3, IgA and IgM responses to 16 Plasmodium falciparum antigens were compared in individuals < 5 years old (80 cases vs. 240 controls), 5-14 years old (103 cases vs. 309 controls) and >= 15 years old (118 cases vs. 354 controls). Antibody level was correlated with risk of clinical malaria, adjusted for malaria exposure markers. Results In all age groups, most antibodies were not associated with risk of clinical malaria. In children < 5 years, higher levels of IgG to GLURP-R2 and MSP-2, IgG1 to GLURP-R2, and IgG3 to MSP-2 were associated with reduced risk of clinical malaria, while higher IgG3 levels to CSP were associated with increased risk of clinical malaria. In children 5-14 years and individuals >= 15 years, higher antibody levels to multiple P. falciparum antigens were associated with an increased risk of clinical malaria, and none were associated with decreased risk of clinical malaria. Conclusions Antibody correlates of protection against clinical malaria were observed only in children < 5 years old in this area of low and unstable malaria transmission. In older children and adults in this area, some antibody responses correlated with increased risk of clinical malaria. Future studies in low malaria transmission areas should evaluate the comparative contributions of cellular and humoral immunity to protection from clinical malaria in young children versus older children and adults.