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.
Highlights
The Plasmodium falciparum Pfs[25] protein (Pfs25) is a leading malaria transmission-blocking vaccine antigen
Fundamental to this idea are transmission-blocking vaccines (TBVs), which seek to inhibit the development of parasites in the mosquito vector to prevent its spread back to the human population
To develop a molecular understanding of the antibody response to Pfs[25], Kymab mice (KymouseTM), that are transgenic for the nonrearranged human antibody germline repertoire, were immunized with a plant-produced Pfs25-viruslike particles (VLPs) immunogen[23]
Summary
The Plasmodium falciparum Pfs[25] protein (Pfs25) is a leading malaria transmission-blocking vaccine antigen. Our structural findings reveal the fine specificities associated with two distinct immunogenic sites on Pfs[25] 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. It is assumed that the most effective path to malaria elimination will involve a combination of immunization strategies effective at blocking several Pf life stages[1,2]. Fundamental to this idea are transmission-blocking vaccines (TBVs), which seek to inhibit the development of parasites in the mosquito vector to prevent its spread back to the human population.
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