Structural delineation of potent transmission-blocking epitope I on malaria antigen Pfs48/45

Prasun Kundu, Anthony Semesi, Matthijs M. Jore, Merribeth J. Morin, Virginia L. Price, Alice Liang, Jingxing Li, Kazutoyo Miura, Robert W. Sauerwein, C. Richter King and Jean-Philippe Julien ()
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Prasun Kundu: The Hospital for Sick Children Research Institute
Anthony Semesi: The Hospital for Sick Children Research Institute
Matthijs M. Jore: Radboud University Medical Center
Merribeth J. Morin: PATH’s Malaria Vaccine Initiative
Virginia L. Price: PATH’s Malaria Vaccine Initiative
Alice Liang: LakePharma Inc.
Jingxing Li: LakePharma Inc.
Kazutoyo Miura: National Institutes of Health
Robert W. Sauerwein: Radboud University Medical Center
C. Richter King: PATH’s Malaria Vaccine Initiative
Jean-Philippe Julien: The Hospital for Sick Children Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract Interventions that can block the transmission of malaria-causing Plasmodium falciparum (Pf) between the human host and Anopheles vector have the potential to reduce the incidence of malaria. Pfs48/45 is a gametocyte surface protein critical for parasite development and transmission, and its targeting by monoclonal antibody (mAb) 85RF45.1 leads to the potent reduction of parasite transmission. Here, we reveal how the Pfs48/45 6C domain adopts a (SAG1)-related-sequence (SRS) fold. We structurally delineate potent epitope I and show how mAb 85RF45.1 recognizes an electronegative surface with nanomolar affinity. Analysis of Pfs48/45 sequences reveals that polymorphisms are rare for residues involved at the binding interface. Humanization of rat-derived mAb 85RF45.1 conserved the mode of recognition and activity of the parental antibody, while also improving its thermostability. Our work has implications for the development of transmission-blocking interventions, both through improving vaccine designs and the testing of passive delivery of mAbs in humans.

Date: 2018
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DOI: 10.1038/s41467-018-06742-9

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