A machine learning framework to identify complex physicochemical features of B cell epitopes

During infection with Plasmodium falciparum in pregnancy, parasites express a unique virulence factor, VAR2CSA, that mediates binding of infected red blood cells to the placenta. A major goal in designing vaccines to protect pregnant women from malaria is to elicit antibodies to VAR2CSA. The challenge is that VAR2CSA is highly polymorphic and identifying conserved epitopes is essential to elicit strain-transcending immunity. Unexpectedly, a mouse monoclonal antibody, 3D10, raised against the unrelated Duffy binding protein from P. vivax (DBPII) cross-reacts with diverse alleles of VAR2CSA in vitro. To identify these potentially conserved epitopes in VAR2CSA, we designed a machine learning framework to analyse 3D10 reactivity to peptides derived from two alleles of VAR2CSA, DBPII, and PvEBP2 (negative control). We used decision trees and a panel of 430 features to extract features correlated to 3D10 binding. We analysed patterns of these features in the dataset and designed mutant peptides to test complex sequence motifs. Features associated with 3D10 reactivity were mapped onto predicted 3D structures of Plasmodium proteins and validated based on 3D10 reactivity to the recombinant antigens. While the array data identified certain linear epitopes, the framework predicted other epitopes that are conformational. With this approach, peptide array data can be mined to extract physicochemical properties of epitopes recognized by polyreactive antibodies.