Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
IGHV3-33-encoded antibodies are prevalent in the human humoral response against the Plasmodium falciparum circumsporozoite protein (PfCSP). Among VH3-33 antibodies, cross-reactivity between PfCSP major repeat (NANP), minor (NVDP), and junctional (NPDP) motifs is associated with high affinity and potent parasite inhibition. However, the molecular basis of antibody cross-reactivity and the relationship with efficacy remain unresolved. Here, we perform an extensive structure-function characterization of 12 VH3-33 anti-PfCSP monoclonal antibodies (mAbs) with varying degrees of cross-reactivity induced by immunization of mice expressing a human immunoglobulin gene repertoire. We identify residues in the antibody paratope that mediate cross-reactive binding and delineate four distinct epitope conformations induced by antibody binding, with one consistently associated with high protective efficacy and another that confers comparably potent inhibition of parasite liver invasion. Our data show a link between molecular features of cross-reactive VH3-33 mAb binding to PfCSP and mAb potency, relevant for the development of antibody-based interventions against malaria.
Date Issued
2023-11-28
Date Acceptance
2023-10-06
Citation
Cell Reports, 2023, 42 (11)
ISSN
2211-1247
Publisher
Elsevier
Journal / Book Title
Cell Reports
Volume
42
Issue
11
Copyright Statement
© 2023 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/38007690
PII: S2211-1247(23)01342-6
Subjects
antibody
circumsporozoite protein
CP: Immunology
CP: Microbiology
cross-reactivity
CSP
Fab structure
malaria
Plasmodium falciparum
repeat motifs
VH3-33 antibodies
Publication Status
Published
Coverage Spatial
United States
Article Number
ARTN 113330
Date Publish Online
2023-10-28