Protective Immunity against Severe Malaria in Children Is Associated with a Limited Repertoire of Antibodies to Conserved PfEMP1 Variants

Sofonias K Tessema; Rie Nakajima; Algis Jasinskas; Stephanie L Monk; Lea Lekieffre; Enmoore Lin; Benson Kiniboro; Carla Proietti; Peter Siba; Philip L Felgner; Denise L Doolan; Ivo Mueller; Alyssa E Barry

doi:10.1016/j.chom.2019.10.012

Protective Immunity against Severe Malaria in Children Is Associated with a Limited Repertoire of Antibodies to Conserved PfEMP1 Variants

Cell Host Microbe. 2019 Nov 13;26(5):579-590.e5. doi: 10.1016/j.chom.2019.10.012.

Authors

Affiliations

¹ Division of Population Health and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3000, VIC, Australia.
² Physiology & Biophysics Department, Vaccine R&D Center, University of California, Irvine, Irvine 92697, CA, USA.
³ Infectious Diseases Programme, QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia.
⁴ Vector Borne Diseases Unit, Papua New Guinea Institute of Medical Research, Goroka 441, EHG, Papua New Guinea.
⁵ Infectious Diseases Programme, QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia; Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4878, QLD, Australia.
⁶ Division of Population Health and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3000, VIC, Australia; Department of Parasites and Insect Vectors, Institut Pasteur, Paris 75015, France.
⁷ Division of Population Health and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne 3000, VIC, Australia. Electronic address: [email protected].

PMID: 31726028
DOI: 10.1016/j.chom.2019.10.012

Abstract

Extreme diversity of the major Plasmodium falciparum antigen, PfEMP1, poses a barrier to identifying targets of immunity to malaria. Here, we used protein microarrays containing hundreds of variants of the DBLα domain of PfEMP1 to cover the diversity of Papua New Guinean (PNG) parasites. Probing the plasma of a longitudinal cohort of malaria-exposed PNG children showed that group 2 DBLα antibodies were moderately associated with a lower risk of uncomplicated malaria, whereas individual variants were only weakly associated with clinical immunity. In contrast, antibodies to 85 individual group 1 and 2 DBLα variants were associated with a 70%-100% reduction in severe malaria. Of these, 17 variants were strong predictors of severe malaria. Analysis of full-length PfEMP1 sequences from PNG samples shows that these 17 variants are linked to pathogenic CIDR domains. This suggests that whereas immunity to uncomplicated malaria requires a broad repertoire of antibodies, immunity to severe malaria targets a subset of conserved variants. These findings provide insights into antimalarial immunity and potential antibody biomarkers for disease risk.

Keywords: PfEMP1; Plasmodium falciparum; antibodies; biomarker; diversity; immunity; malaria; severe malaria; vaccine; var genes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Protozoan / blood
Antibodies, Protozoan / immunology*
Antigens, Protozoan / genetics
Antigens, Protozoan / immunology*
Child, Preschool
Female
Humans
Infant
Longitudinal Studies
Malaria Vaccines / immunology
Malaria, Falciparum / immunology
Malaria, Falciparum / prevention & control
Male
Papua New Guinea
Plasmodium falciparum / immunology*
Protein Array Analysis
Protein Domains / genetics
Protein Domains / immunology*
Protozoan Proteins / genetics
Protozoan Proteins / immunology*

Substances

Antibodies, Protozoan
Antigens, Protozoan
Malaria Vaccines
Protozoan Proteins
erythrocyte membrane protein 1, Plasmodium falciparum