Parasite variant surface antigen expression and immune gaps in severe malaria

Severe malaria kills hundreds of thousands of children across sub-Saharan Africa annually, accounting for most malaria-related deaths globally. The exact parasite genes responsible for severe disease that could be targets for vaccine or drug development have not yet been identified. Parasite variant surface antigens – genetically diverse malaria proteins expressed on the surface of infected erythrocytes – appear to play a critical role in severe malaria pathogenesis. A novel strategy was recently developed to de novo sequence variant surface antigen transcripts from whole blood using RNA-seq with a custom capture array to enrich for variant surface antigen detection. The newly developed capacity to determine full-length transcripts present in severe malaria infections enables comprehensive identification of gene expression signatures for clinical syndromes and for comparisons of such signatures across severe malaria subtypes and different geographies. Using this approach in Mali, parasite variant surface antigens expressed solely in severe disease and other variant surface antigens differentially expressed in severe versus mild disease were identified that are known to target multiple human host receptors. The central hypothesis is that severe malarial disease is the result of a subset of virulent parasite variant surface antigens that are common across sub-Saharan Africa. The variant surface antigen transcripts will be sequenced in severe malaria cases and matched uncomplicated malaria controls in Zambian children and adults (Aim 1). Then a custom protein microarray featuring a comprehensive representation of variant surface antigens will be used to determine the malaria parasite variant surface antigens associated with increased vulnerability to severe malarial in Zambian children and adults (Aim 2). This microarray will be populated with severe disease variant surface antigens from Zambia sequenced in Aim 1, from Mali and Malawi (previously sequenced), and from reference strains, as well as a broad selection of additional reactive malaria antigens from all parasite lifecycle stages. The data generated from this R21 study will be used to form the basis of an R01 proposal to identify common subsets of parasite variant surface antigens associated with severe malaria in children and adults across Africa that could form the basis of a vaccine or biologic.

NIH Project details

Basic Science
Vaccines (Immune Correlates)

Jul 2024 — May 2026

$226,991

Malawi
Mali
Zambia