Abstract
Naturally acquired clinical immunity to Plasmodium falciparum is partly mediated by antibodies directed at parasite-derived antigens expressed on the surface of red blood cells which mediate disease and are extremely diverse. Unlike children, adults recognize a broad range of variant surface antigens (VSAs) and are protected from severe disease. Though crucial to the design and feasibility of an effective malaria vaccine, it is not yet known whether immunity arises through cumulative exposure to each of many antigenic types, cross-reactivity between antigenic types, or some other mechanism. In this study, we measured plasma antibody responses of 36 children with symptomatic malaria to a diverse panel of 36 recombinant proteins comprising part of the DBLα domain (the ‘DBLα-tag’) of PfEMP1, a major class of VSAs. We found that although plasma antibody responses were highly specific to individual antigens, serological profiles of responses across antigens fell into one of just two distinct types. One type was found almost exclusively in children that succumbed to severe disease (19 out of 20) while the other occurred in all children with mild disease (16 out of 16). Moreover, children with severe malaria had serological profiles that were narrower in antigen specificity and shorter-lived than those in children with mild malaria. Borrowing a novel technique used in influenza–antigenic cartography—we mapped these dichotomous serological profiles to amino acid sequence variation within a small sub-region of the PfEMP1 DBLα domain. By applying our methodology on a larger scale, it should be possible to identify epitopes responsible for eliciting the protective version of serological profiles to PfEMP1 thereby accelerating development of a broadly effective anti-disease malaria vaccine.
Highlights
The surface of red blood cells (RBCs) infected with Plasmodium falciparum contains antigens of parasite origin that are highly immunogenic and genetically very diverse [1]
Protection against severe disease occurs early in life in malaria-endemic areas. Both anti-infection and anti-disease immunity depend on antibody responses to proteins expressed by the parasite on the red blood cell surface which cause pathology
By applying a novel technique used for describing antigenic diversity in influenza viruses–antigenic cartography— we make the surprising discoveries that children’s serological responses to a panel of diverse surface antigens fall into one of just two qualitatively distinct patterns, and that these almost perfectly predict severity of disease
Summary
The surface of red blood cells (RBCs) infected with Plasmodium falciparum contains antigens of parasite origin that are highly immunogenic and genetically very diverse [1]. PfEMP1 is encoded by approximately 60 var genes which are genetically diverse within and between parasite genomes, and which recombine, potentially presenting a challenge in finding a handful of antigens that could form the basis of a broadly effective vaccine Despite their genetic diversity, var genes structure into distinct groups somewhat limiting this pool of variability. Var genes structure into distinct groups somewhat limiting this pool of variability These groupings are based on chromosomal position and upstream sequence (Ups) [5,6]; combinations of domains and sub-domains (domain cassettes, DC) [5,7,8,9]; and homology in short sequence blocks found across the full gene (‘homology blocks’, HB) [7,9] or at positions of limited variability (PoLV) within the DBLα domain [10]. PfEMP1 host cell adhesion phenotypes ICAM-1, EPCR and rosetting have been mapped to expression of specific domains or domain cassettes providing a clear link between PfEMP1 diversity, adhesion phenotype and disease severity [4]
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