Abstract
BackgroundAntibody immunity is thought to be essential to prevent severe Plasmodium falciparum infection, but the exact correlates of protection are unknown. Over time, children in endemic areas acquire non-sterile immunity to malaria that correlates with development of antibodies to merozoite invasion proteins and parasite proteins expressed on the surface of infected erythrocytes.ResultsA 1000 feature P. falciparum 3D7 protein microarray was used to compare P. falciparum-specific seroreactivity during acute infection and 30 days after infection in 23 children with uncomplicated malaria (UM) and 25 children with retinopathy-positive cerebral malaria (CM). All children had broad P. falciparum antibody reactivity during acute disease. IgM reactivity decreased and IgG reactivity increased in convalescence. Antibody reactivity to CIDR domains of “virulent” PfEMP1 proteins was low with robust reactivity to the highly conserved, intracellular ATS domain of PfEMP1 in both groups. Although children with UM and CM differed markedly in parasite burden and PfEMP1 exposure during acute disease, neither acute nor convalescent PfEMP1 seroreactivity differed between groups. Greater seroprevalence to a conserved Group A-associated ICAM binding extracellular domain was observed relative to linked extracellular CIDRα1 domains in both case groups. Pooled immune IgG from Malawian adults revealed greater reactivity to PfEMP1 than observed in children.ConclusionsChildren with uncomplicated and cerebral malaria have similar breadth and magnitude of P. falciparum antibody reactivity. The utility of protein microarrays to measure serological recognition of polymorphic PfEMP1 antigens needs to be studied further, but the study findings support the hypothesis that conserved domains of PfEMP1 are more prominent targets of cross reactive antibodies than variable domains in children with symptomatic malaria. Protein microarrays represent an additional tool to identify cross-reactive Plasmodium antigens including PfEMP1 domains that can be investigated as strain-transcendent vaccine candidates.
Highlights
Antibody immunity is thought to be essential to prevent severe Plasmodium falciparum infection, but the exact correlates of protection are unknown
The study results indicate that children with uncomplicated malaria (UM) and cerebral malaria (CM) have broad seroreactivity to the panel of ~ 1000 P. falciparum antigens and have lowest seroreactivity during acute disease to endothelial protein C receptor (EPCR)-binding “virulent” PfEMP1 antigens represented on the array [17, 25]
Of 38 UM and 57 ret + CM cases, cases were selected for inclusion if they met all of the following criteria: (1) attended 30 day follow-up appointment, (2) HIV non-reactive, (3) successful var qRT-PCR typing from acute infection, and (4) sufficient acute and convalescent plasma for the study
Summary
Antibody immunity is thought to be essential to prevent severe Plasmodium falciparum infection, but the exact correlates of protection are unknown. Children in endemic areas acquire non-sterile immunity to malaria that correlates with development of antibodies to merozoite invasion proteins and parasite proteins expressed on the surface of infected erythrocytes. Antibody immunity to Plasmodium falciparum malaria is central to the prevention and clearance of symptomatic disease [1], but is acquired only after years of exposure [2]. Immunity to malaria is non-sterile, and older children and adults in malaria-endemic areas are frequently parasitaemic, but asymptomatic. Children in sub-Saharan Africa carry the burden of morbidity and mortality associated with P. falciparum infection [3]. It is still unclear why some parasitaemic children develop severe malarial syndromes, including cerebral malaria (CM). A subsequent 824 feature array representing 699 Pf genes was down-selected on the basis of initial array data [5]
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