Antibodies to repeat-containing antigens in Plasmodium falciparum are exposure-dependent and short-lived in children in natural malaria infections

• DOI: 10.7554/elife.81401
• Publication Date: 2023-02-15T13:00:28Z
• Authors: Madhura Raghavan; Katrina L Kalantar; Elias Duarte; Noam Teyssier; Saki Takahashi; Andrew F Kung; Jayant V Rajan; John Rek; Kevin KA Tetteh; Chris Drakeley; Isaac Ssewanyana; Isabel Rodriguez-...; Bryan Greenhouse; Joseph L DeRisi
• Keywords: 0301 basic medicine; Protozoan Proteins; Antibodies, Protozoan; Malaria vaccine; immunology; Epitopes; falciparum; Immunology and Inflammation; Role of Complement System in Immune Response; 2.1 Biological and endogenous factors; antibodies; Aetiology; Biology (General); Malaria, Falciparum; Child; Pediatric; Immunology and Microbiology; 0303 health sciences; Q; R; Life Sciences; P; 3. Good health; repeat regions; Infectious Diseases; Antigen; Protozoan; HIV/AIDS; Medicine; Epitope; antigen profiling; phage display; Infection; Biotechnology; Human; Falciparum; Adult; 570; QH301-705.5; infectious disease; Science; Immunology; Plasmodium falciparum; malaria; 610; Antigens, Protozoan; P. falciparum; Antibodies; 03 medical and health sciences; Rare Diseases; Virology; Health Sciences; Genetics; Humans; human; Antigens; Biology; Antibody; FOS: Clinical medicine; microbiology; Public Health, Environmental and Occupational Health; Immunity; Malaria; Vector-Borne Diseases; natural immunity; Good Health and Well Being; Immune system; inflammation; FOS: Biological sciences; Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome; Immunization; Biochemistry and Cell Biology

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.