Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure

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.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2323-4) contains supplementary material, which is available to authorized users.

Protective Immunity against Severe Malaria in Children Is Associated with a Limited Repertoire of Antibodies to Conserved PfEMP1 Variants

“…For clinical malaria, antibody levels to any of the individual DBLa variants or subgroups had a poor predictive power (AUC = 0.5-0.57). In fact, mol FOB was the major predictor of clinical malaria (AUC = 0.8), but this was not the case for severe malaria (AUC = 0.49) and is consistent with previous findings (Kessler et al, 2018) (Figure S7).…”

“…A recent study in Papua New Guinean (PNG) children showed that naturally acquired PfEMP1 antibodies expressed on the surface of infected red blood cells play a role in protection from severe malaria (Chan et al, 2012;Chan et al, 2017). Still, there have been conflicting reports on the associations between antibodies to recombinant PfEMP1 domains from the 3D7 reference isolate and protection from clinical and severe malaria (Kessler et al, 2018;Rambhatla et al, 2019;Travassos et al, 2018). This discrepancy might emanate from (1) the use of PfEMP1 antigens derived from laboratory-adapted strains that are evolutionarily distant from strains infecting the studied human population and (2) the lack of accurate measures of individual exposure to malaria, which influences antibody levels over time (Stanisic et al, 2015).…”

Acquisition of IgG to ICAM-1-Binding DBLβ Domains in the Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigen Family Varies between Groups A, B, and C

“…In agreement with this, a recent study found that children with uncomplicated and cerebral malaria had similar breadth and magnitude of responses to different P. falciparum antigens, including DBLβ domains (35). Finally, our data suggest that IgG specific for ICAM-1-binding DBLβ domains from group A and associated specifically with cerebral malaria (18) is acquired later in life than IgG specific for ICAM-1-binding DBLβ domains from group B and C PfEMP1 (Fig.…”

“…Of the two domain types, CIDRα domains are more commonly recognized than DBL domains (12, 32), and some studies have shown acquisition of group A CIDRα1-specific IgG to precede immunity to group B and C CIDRα2-6 domains (33), while others found no such link (12, 34). Two recent studies found similar antibody reactivity against group A CIDRα1 in uncomplicated and severe malaria during acute disease (34, 35), while at convalescence older children with severe (likely noncerebral) malaria had higher antibody levels against such EPCR binding CIDRα1 than those with uncomplicated malaria (34). The PfEMP1 reactivity between convalescent groups did not differ in the study by Kessler et al (35), although higher seroprevalence to the conserved group A-associated ICAM-1-binding DBLβ domain (18) was observed relative to that of CIDRα1.…”

Antibodies to Peptides in Semiconserved Domains of RIFINs and STEVORs Correlate with Malaria Exposure

“…Our goal was to identify the RIFIN and STEVOR domains and amino acid residues that contain epitopes reflecting malaria exposure. We hypothesized that antibodies against RIFINs and STEVORs would target more epitopes within the SC domain than within the V1 and V2 domains, given the SC domain’s membrane orientation and relative sequence homology ( 18 , 27 , 28 ).…”