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

Fabra-García, Amanda; Hailemariam, Sophia; Jong, Roos M. de; Janssen, Kirsten; Teelen, Karina; Vegte‐Bolmer, Marga van de; Gemert, Geert-Jan van; Ivanochko, Danton; Semesi, A.; McLeod, Brandon; Vos, Martijn; Bruijni, Marloes H.C. de; Bolscher, Judith M.; Szabat, Marta; Vogt, Stefanie; Kraft, Lucas; Duncan, Sherie; Kamya, Moses R.; Feeney, Margaret E.; Jagannathan, Prasanna; Greenhouse, Bryan; Dechering, Koen J.; Sauerwein, Robert W.; King, C. Richter; MacGill, Randall S.; Bousema, Teun; Julien, Jean-Philippe; Jore, Matthijs M.

doi:10.1016/j.immuni.2023.01.009

Cited by 19 publications

(27 citation statements)

References 49 publications

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“…2E) . This is in agreement with prior work indicating mAbs to Domain 2 of Pfs48/45 are generally mAbs with low potency (27).…”

Section: Resultssupporting

confidence: 93%

“…Among the seven mAbs exhibiting TRA, three were found to recognize the well-defined TRA targets Pfs48/45 and Pfs230. The B1C5L and B1C5K mAbs were shown to recognize Domain 2 of Pfs48/45 and exhibited moderate potency, as previously described for Abs with such specificity (27). These 2 mAbs were isolated from the same well and shared the same heavy chain; their similar characteristics thus suggest that their binding is primarily mediated by the heavy chain.…”

Section: Discussionsupporting

confidence: 62%

“…Furthermore, a mAb identical to B1C5K was recently isolated from the same donor using a single B cell selection approach with recombinant Pfs48/45 (27). Pfs230 was shown, via SIFA and Western blot, to be targeted by the B2C10L mAb, which failed to bind the D1 domain in ELISA.…”

Section: Discussionmentioning

confidence: 99%

“…Gamete or gametocyte lysate were prepared as described (27). Three hundred eighty four well plates (Thermo Fisher Scientific #460372) were coated with 7500 lysed gametes / gametocytes per well.…”

Section: Gamete / Gametocyte Extract Elisamentioning

confidence: 99%

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Target-agnostic identification of human antibodies toPlasmodium falciparumsexual forms reveals cross stage recognition of glutamate-rich repeats

Amen,

Yoo,

Fabra-García

et al. 2023

Preprint

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Circulating sexual stages ofPlasmodium falciparum (Pf)can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies (Abs) can efficiently block parasite transmission. In search for naturally acquired Ab targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to natural sexual stages ofPfin the form of gamete and gametocyte extract. We isolated mAbs reactive against a range ofPfproteins including well-established targets Pfs48/45 and Pfs230. One of these mAbs, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition ofPfproteins, previously described only for PfCSP, extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of thePlasmodiumparasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response againstPf.SummaryProteins with amino acid repeats enriched in glutamate residues are prominently expressed in the asexual and sexual stages ofPlasmodium falciparum(Pf), the main causative agent of malaria. Here, we present a target-agnostic approach for the isolation of sexual stage antibodies (Abs), leading to the identification of B1E11K, an Ab cross-reactive to glutamate-rich repeats in proteins present in various life cycle stages ofPf. The Ab binds in a head-to-head conformation, leveraging affinity-matured homotypic interactions – an uncommon characteristic of Ab somatic hypermutation that results in the optimization of Ab-Ab interactions in the context of binding their repetitive epitope. Our data provides further credence that repetitive elements ofPfcan significantly modulate the humoral response, and that antibody recognition through homotypic interactions is occurring throughout thePflife cycle.

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“…2E) . This is in agreement with prior work indicating mAbs to Domain 2 of Pfs48/45 are generally mAbs with low potency (27).…”

Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Gamete / Gametocyte Extract Elisamentioning

confidence: 99%

See 2 more Smart Citations

Target-agnostic identification of human antibodies toPlasmodium falciparumsexual forms reveals cross stage recognition of glutamate-rich repeats

Amen,

Yoo,

Fabra-García

et al. 2023

Preprint

Self Cite

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show abstract

“…Antibodies targeting all the domains of Pfs48/45 have been identi ed with varying degrees of transmission-reducing activity (TRA), yet the relationship between epitope and antibody potency remains poorly understood, particularly for Domains 1 and 2 (D1 and D2) 26,27 . For example, from a panel of 16 mAbs derived from mice immunized with recombinant full-length Pfs48/45 expressed from Drosophila melanogaster S2 cells, only one mAb was detected to possess signi cant TRA when assessed at 350 µg/ml 23 .…”

Section: Introductionmentioning

confidence: 99%

Structural elucidation of full-length Pfs48/45 in complex with potent mAbs isolated from a naturally exposed individual

Julien,

Kucharska,

Ivanochko

et al. 2023

Preprint

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Biomedical interventions capable of preventing the transmission of malaria-causing Plasmodium falciparum (Pf) between the human host and mosquito vector could prove a valuable tool in malaria elimination efforts. Pfs48/45, a gamete-surface protein essential for Pf development in the mosquito midgut, is a key component of clinical-stage transmission-blocking vaccines. Antibodies against this antigen have been demonstrated to efficiently reduce Pf transmission from humans to mosquitoes. Potent human monoclonal antibodies (mAbs) against Domain 3 (D3) of Pfs48/45 have been structurally and functionally described; however, in-depth information about other inhibitory epitopes on Pfs48/45 is currently limited. Here, we present a 3.3 Å resolution cryo-electron microscopy structure of full-length Pfs48/45 in complex with potent mAbs targeting Domain 1 (D1) and D3, and a moderately potent mAb targeting Domain 2 (D2). Our data indicate that while Pfs48/45 D1 and D2 are rigidly coupled, there is substantial conformational flexibility between D2 and D3. Characterization of mAbs against D1 revealed the presence of a conformational epitope class that is largely conserved across Pf field isolates and is associated with recognition by highly potent antibodies. Our study provides comprehensive insights into epitopes across full-length Pfs48/45 and has implications for the design of next-generation malaria transmission-blocking vaccines and antibodies.

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

Ciubotariu,

Broyles,

Xie

et al. 2024

eBioMedicine

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

Cited by 19 publications

References 49 publications

Target-agnostic identification of human antibodies toPlasmodium falciparumsexual forms reveals cross stage recognition of glutamate-rich repeats

Target-agnostic identification of human antibodies toPlasmodium falciparumsexual forms reveals cross stage recognition of glutamate-rich repeats

Structural elucidation of full-length Pfs48/45 in complex with potent mAbs isolated from a naturally exposed individual

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

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