Molecular definition of multiple sites of antibody inhibition of malaria transmission-blocking vaccine antigen Pfs25

Stephen W. Scally, Brandon McLeod, Alexandre Bosch, Kazutoyo Miura, Qi Liang, Sean Carroll, Sini Reponen, Ngan Nguyen, Eldar Giladi, Sebastian Rämisch, Vidadi Yusibov, Allan Bradley, Franck Lemiale, William R. Schief, Daniel Emerling, Paul Kellam, C. Richter King and Jean-Philippe Julien ()
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Stephen W. Scally: The Hospital for Sick Children Research Institute
Brandon McLeod: The Hospital for Sick Children Research Institute
Alexandre Bosch: The Hospital for Sick Children Research Institute
Kazutoyo Miura: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Qi Liang: Kymab Ltd.
Sean Carroll: Atreca
Sini Reponen: Atreca
Ngan Nguyen: Atreca
Eldar Giladi: Atreca
Sebastian Rämisch: The Scripps Research Institute
Vidadi Yusibov: Fraunhofer USA Center for Molecular Biotechnology CMB
Allan Bradley: Kymab Ltd.
Franck Lemiale: PATH’s Malaria Vaccine Initiative
William R. Schief: The Scripps Research Institute
Daniel Emerling: Atreca
Paul Kellam: Kymab Ltd.
C. Richter King: PATH’s Malaria Vaccine Initiative
Jean-Philippe Julien: The Hospital for Sick Children Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract The Plasmodium falciparum Pfs25 protein (Pfs25) is a leading malaria transmission-blocking vaccine antigen. Pfs25 vaccination is intended to elicit antibodies that inhibit parasite development when ingested by Anopheles mosquitoes during blood meals. The Pfs25 three-dimensional structure has remained elusive, hampering a molecular understanding of its function and limiting immunogen design. We report six crystal structures of Pfs25 in complex with antibodies elicited by immunization via Pfs25 virus-like particles in human immunoglobulin loci transgenic mice. Our structural findings reveal the fine specificities associated with two distinct immunogenic sites on Pfs25. Importantly, one of these sites broadly overlaps with the epitope of the well-known 4B7 mouse antibody, which can be targeted simultaneously by antibodies that target a non-overlapping site to additively increase parasite inhibition. Our molecular characterization of inhibitory antibodies informs on the natural disposition of Pfs25 on the surface of ookinetes and provides the structural blueprints to design next-generation immunogens.

Date: 2017
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DOI: 10.1038/s41467-017-01924-3

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