Immunoglobulin G Antibody Reactivity to a Group A Plasmodium falciparum Erythrocyte Membrane Protein 1 and Protection from P. falciparum Malaria

Abstract

Variant surface antigens (VSA) on the surface of Plasmodium falciparum-infected red blood cells play a major role in the pathogenesis of malaria and are key targets for acquired immunity. The best-characterized VSA belong to the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. In areas where P. falciparum is endemic, parasites causing severe malaria and malaria in young children with limited immunity tend to express semiconserved PfEMP1 molecules encoded by group A var genes. Here we investigated antibody responses of Tanzanians who were 0 to 19 years old to PF11_0008, a group A PfEMP1. PF11_0008 has previously been found to be highly transcribed in a nonimmune Dutch volunteer experimentally infected with NF54 parasites. A high proportion of the Tanzanian donors had antibodies against recombinant PF11_0008 domains, and in children who were 4 to 9 years old the presence of antibodies to the PF11_0008 CIDR2␤ domain was associated with reduced numbers of malaria episodes. These results indicate that homologues of PF11_0008 are present in P. falciparum field isolates and suggest that PF11_0008 CIDR2␤-reactive antibodies might be involved in protection against malaria episodes.

Sequential, Ordered Acquisition of Antibodies to Plasmodium falciparum Erythrocyte Membrane Protein 1 Domains

“…The DBL2␥ domain of PF11_0008 was the best recognized domain, and after the first year of life Ͼ60% of the children in the high transmission villages had acquired Abs against this domain. We have previously shown that the presence of Abs to PF11_0008 was associated with protection against malaria fevers (41). In the age group 2-3 years, DBL5 of MAL6P1.4 was recognized by about half of the children in the high transmission village and by more than a third of the children in the medium transmission villages.…”

Hierarchical, Domain Type-Specific Acquisition of Antibodies to Plasmodium falciparum Erythrocyte Membrane Protein 1 in Tanzanian Children

“…After the first years of life, the children become far less vulnerable to severe noncerebral malaria, and in the following years, their risk of developing uncomplicated malaria diminishes progressively as they acquire immunity (3). Acquired malaria immunity is mediated at least in part by IgG (9,35), and several studies indicate that PfEMP1 variants are important targets (5,26,27). This is best demonstrated by the high susceptibility to infection in first-time pregnant women, in which parasites expressing a particular pregnancy-specific PfEMP1 variant, VAR2CSA, can sequester in the placenta (11).…”

“…Sequestration is undoubtedly an important element in malaria pathogenesis (6,11,28,31), and acquisition of PfEMP1-specific antibodies therefore appears to be a critical element in naturally acquired protective immunity to the disease (5,26,27,36). Interestingly, acquisition of clinical immunity to severe complications precedes protection from uncomplicated disease and asymptomatic parasitemia (2,14).…”

Acquired Immunity to Malaria

“…VSA expressed during episodes of clinical malaria in Kenyan children were less likely to be recognized by the preexisting antibodies in the same child than that by other children, as assessed by agglutination (52), and agglutination by diverse plasma was associated with severe disease and young host age (51). Anti-VSA IgG levels have been correlated with protection from clinical malaria in Ghana (102,232), Kenya (169), Gabon (324), and Tanzania (187). A recent study with malaria-naive humans experiencing a single P. falciparum infection demonstrated antibody reactive with up to six P. falciparum lines expressing different heterologous PfEMP1 variants (112).…”