Structure of the malaria vaccine candidate Pfs48/45 and its recognition by transmission blocking antibodies

Abstract

An effective malaria vaccine remains a global health priority and vaccine immunogens which prevent transmission of the parasite will have important roles in multi-component vaccines. One of the most promising candidates for inclusion in a transmission-blocking malaria vaccine is the gamete surface protein Pfs48/45, which is essential for development of the parasite in the mosquito midgut. Indeed, antibodies which bind Pfs48/45 can prevent transmission if ingested with the parasite as part of the mosquito bloodmeal. Here we present the structure of full-length Pfs48/45, showing its three domains to form a dynamic, planar, triangular arrangement. We reveal where transmission-blocking and non-blocking antibodies bind on Pfs48/45. Finally, we demonstrate that antibodies which bind across this molecule can be transmission-blocking. These studies will guide the development of future Pfs48/45-based vaccine immunogens.

Highly potent, naturally acquired human monoclonal antibodies against Pfs48/45 block Plasmodium falciparum transmission to mosquitoes

“…Some mAbs against D1 and D3 competed with each other, suggesting that these domains may be in close proximity, which is supported by recent X-ray crystallography structures of full-length Pfs48/45 in the context of mouse-derived antibodies of varying potencies. 28 An overlay of the co-crystal structures of D3 bound to RUPA-29, RUPA-44, RUPA-117, and RUPA-47 with the full-length crystal structure of Pfs48/45 28 indicates that these two potent epitopes are accessible in the full-length Pfs48/45 structure, as would be expected ( Figure S4 E).…”

“…To date, our molecular understanding of P. falciparum transmission inhibition as mediated by antibody binding to Pfs48/45-D3 has been limited to crystal structures of D3 in complex with three Fabs: 85RF45.1 (PDB: 6H5N and 6E62), TB31F (PDB: 6E63), and 32F3 (PDB: 7ZWI), which all target epitope I on D3. 11 , 18 , 28 To expand on this knowledge, we solved structures of two ternary complexes: D3 bound to RUPA-47 Fab and RUPA-117 Fab, and D3 bound to RUPA-29 Fab and RUPA-44 Fab, at resolutions of 2.18 and 2.86 Å, respectively ( Figures S4A-S4D ; Table S3 ; PDB: 7UNB). 29 …”

Diversity and selection analyses identify transmission-blocking antigens as the optimal vaccine candidates inPlasmodium falciparum

“…In contrast, both Pfs48/45 and Pfs230 are essential antigens for P. falciparum life cycle 95,96 . Potent transmission-blocking antibodies have been characterized for Pfs48/45 83,97,98 , Pfs230 (D1, D2) 99–101 , and Pfs47 102 . As reported above, we only found signals of weak or no balancing selection in these three antigens where potent antibodies are binding.…”

A previously-unrecognized motif of transcription factor RYBP, hotspot of cancer-related mutations, is essential for the integrity ofPolycombrepressive complex 1

“…In the last couple of years, AlphaFold2 has already proven to be a crucial tool in structural biology, because the resulting predicted structures can be used as starting models for molecular replacement in X-ray crystallography, for modelling cryo-electron microscopy 3D reconstructions or SAXS 3D volumes, and for the rational design of mutations and functional assays. For example, AlphaFold2 helped deciphering the structure of the human nuclear pore complex (Mosalaganti et al, 2022) or of the full-length gamete surface protein Pfs48/45, a malaria vaccine candidate (Ko et al, 2022). Our study adds to such already remarkable impact, by providing an example of how AlphaFold2 can identify putatively structured regions embedded in regions of high intrinsic disorder.…”