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The Stability and Complexity of Antibody Responses to the Major Surface Antigen of Plasmodium falciparum Are Associated with Age in a Malaria Endemic Area*

https://doi.org/10.1074/mcp.M111.008326Get rights and content
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Individuals that are exposed to malaria eventually develop immunity to the disease with one possible mechanism being the gradual acquisition of antibodies to the range of parasite variant surface antigens in their local area. Major antibody targets include the large and highly polymorphic Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family of proteins. Here, we use a protein microarray containing 123 recombinant PfEMP1-DBLα domains (VAR) from Papua New Guinea to seroprofile 38 nonimmune children (<4 years) and 29 hyperimmune adults (≥15 years) from the same local area. The overall magnitude, prevalence and breadth of antibody response to VAR was limited at <2 years and 2–2.9 years, peaked at 3–4 years and decreased for adults compared with the oldest children. An increasing proportion of individuals recognized large numbers of VAR proteins (>20) with age, consistent with the breadth of response stabilizing with age. In addition, the antibody response was limited in uninfected children compared with infected children but was similar in adults irrespective of infection status. Analysis of the variant-specific response confirmed that the antibody signature expands with age and infection. This also revealed that the antibody signatures of the youngest children overlapped substantially, suggesting that they are exposed to the same subset of PfEMP1 variants. VAR proteins were either seroprevalent from early in life, (<3 years), from later in childhood (≥3 years) or rarely recognized. Group 2 VAR proteins (Cys2/MFK-REY+) were serodominant in infants (<1-year-old) and all other sequence subgroups became more seroprevalent with age. The results confirm that the anti-PfEMP1-DBLα antibody responses increase in magnitude and prevalence with age and further demonstrate that they increase in stability and complexity. The protein microarray approach provides a unique platform to rapidly profile variant-specific antibodies to malaria and suggests novel insights into the acquisition of immunity to malaria.

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This work was supported by the National Health and Medical Research Council of Australia (NHMRC, Project Grants 496600 and 1005653; http://www.nhmrc.gov.au) and the National Institute of Allergy and Infectious Diseases (Grant R43AI066791-01; http://www.nih.gov.au). Samples were collected with funding from a Wellcome Trust Project Grant awarded to KPD. AEB was supported by an Innovation Fellowship from the Victorian Endowment for Science Knowledge and Innovation and a Howard Florey Centenary Fellowship from the NHMRC. FJIF is supported by a training fellowship from the NHMRC. DLD is supported by a Pfizer Australia Senior Research Fellowship. We gratefully acknowledge the contribution of the Victorian Operational Infrastructure Support Program, through the Burnet Institute.

This article contains supplemental Figs. S1 to S5 and Tables S1 and S2.

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Current address: Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052.