Proteome-wide antigenic profiling in Ugandan cohorts identifies associations between age, exposure intensity, and responses to repeat-containing antigens in Plasmodium falciparum

Protection against Plasmodium falciparum, which is primarily
antibody-mediated, requires recurrent exposure to develop. The study of
both naturally acquired limited immunity and vaccine induced protection
against malaria remains critical for ongoing eradication efforts. Towards
this goal, we deployed a customized P.
falciparum PhIP-seq T7 phage display library
containing 238,068 tiled 62-amino acid peptides,
covering all known coding regions, including antigenic variants, to
systematically profile antibody targets in 198 Ugandan children and adults
from high and moderate transmission settings. Repeat elements –
short amino acid sequences repeated within a protein – were significantly
enriched in antibody targets. While breadth of responses to
repeat-containing peptides was twofold higher in children living
in the high versus moderate exposure setting, no such differences were
observed for peptides without repeats, suggesting that antibody
responses to repeat-containing regions may be more exposure dependent
and/or less durable in children than responses to regions without
repeats. Additionally, short motifs associated with
seroreactivity were extensively shared among hundreds of antigens,
potentially representing cross-reactive epitopes. PfEMP1 shared
motifs with the greatest number of other antigens, partly driven
by the diversity of PfEMP1 sequences. These data suggest that the large
number of repeat elements and potential cross-reactive epitopes found
within antigenic regions of P.
falciparum could contribute to the inefficient nature of
malaria immunity.