Potent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230

Ivanochko, Danton; Fabra-García, Amanda; Teelen, Karina; Vegte‐Bolmer, Marga van de; Gemert, Geert-Jan van; Newton, Jocelyn C.; Semesi, A.; Bruijni, Marloes de; Bolscher, Judith M.; Ramjith, Jordache; Szabat, Marta; Vogt, Stefanie; Kraft, Lucas; Duncan, Sherie; Lee, Shwu-Maan; Kamya, Moses R.; Feeney, Margaret E.; Jagannathan, Prasanna; Greenhouse, Bryan; Sauerwein, Robert W.; King, C. Richter; MacGill, Randall S.; Bousema, Teun; Jore, Matthijs M.; Julien, Jean-Philippe

doi:10.1016/j.immuni.2023.01.013

Cited by 16 publications

(7 citation statements)

References 77 publications

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“…This result was consistent with the findings from SIFA, providing further validation of the specificity of the B1C5K and B1C5L mAbs in targeting Pfs48/45. The B2C10L mAb displayed pattern of recognition that corresponded to Pfs230, similar to the anti-Pfs230 control mAb RUPA-96 (26). Once again, these results were in agreement with the findings from SIFA confirming the specificity of the B2C10L mAb in targeting Pfs230.…”

Section: Sexual Stage Proteinssupporting

confidence: 85%

“…The goal of TBVs is to elicit antibodies that target sexual stage antigens to block the reproduction of the parasite in the mosquito and thus onward transmission to humans. Current TBV development efforts are primarily focused on two antigens, Pfs230 and Pfs48/45, as they are the targets of the most potent transmission-blocking antibodies identified to date (25) (26) (27) (28). Indeed, individuals with sera enriched in antibodies that target Pfs230 and Pfs48/45 were found to have high transmission-reducing activity (29).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, individuals with sera enriched in antibodies that target Pfs230 and Pfs48/45 were found to have high transmission-reducing activity (29). Protective responses to Pfs230 and Pfs48/45 are well characterized at a molecular and structural level (26) (27) (28) (30) (31) (32) (33) (34). However, sera depleted in antibodies targeting the pro domain and domain 1 of Pfs230 and domains 2 and 3 of Pfs48/45 can retain transmission-reducing activity while maintaining the ability to recognize the surface of parasites lacking Pfs48/45 and Pfs230 surface expression (29).…”

Section: Introductionmentioning

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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Section: Sexual Stage Proteinssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Polymorphic residues on domain 3 of Pfs48/45 in our dataset were found not to affect binding affinity severely and the antibodies retained nanomolar affinity ranges 97 . In Pfs230 , some of the potent transmission-blocking antibodies raised from natural exposure bound to regions with no polymorphism in our study 100 , while other potent antibodies raised from human vaccine trials bound to polymorphic regions 101 . Among the polymorphic sites, (Pf3D7 G605S, D714N) were shown to affect binding, while (Pf3D7 E654K, E655V, and A699T) did not.…”

Section: Discussionmentioning

confidence: 55%

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

Ciubotariu,

Broyles,

Xie

et al. 2024

Preprint

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Background A highly effective vaccine for malaria remains an elusive target, at least in part due to the under-appreciated natural parasite variation. This study aimed to investigate genetic and structural variation, and immune selection of leading malaria vaccine candidates across the Plasmodium falciparum life cycle. Methods We analyzed 325 P. falciparum whole genome sequences from Zambia, in addition to 791 genomes from five other African countries available in the MalariaGEN Pf3k Rdatabase. Ten vaccine antigens spanning three life-history stages were examined for genetic and structural variations, using population genetics measures, haplotype network analysis, and 3D structure selection analysis. Findings Among the ten antigens analyzed, only three in the transmission-blocking vaccine category display P. falciparum 3D7 as the dominant haplotype. The antigens AMA1, CSP, MSP119 and CelTOS, are much more diverse than the other antigens, and their epitope regions are under moderate to strong balancing selection. In contrast, Rh5, a blood stage antigen, displays low diversity yet slightly stronger immune selection in the merozoite-blocking epitope region. Except for CelTOS, the transmission-blocking antigens Pfs25, Pfs48/45, Pfs230, Pfs47, and Pfs28 exhibit minimal diversity and no immune selection in epitopes that induce strain-transcending antibodies, suggesting potential effectiveness of 3D7-based vaccines in blocking transmission. Interpretations These findings offer valuable insights into the selection of optimal vaccine candidates against P. falciparum. Based on our results, we recommend prioritizing conserved merozoite antigens and transmission-blocking antigens. Combining these antigens in multi-stage approaches may be particularly promising for malaria vaccine development initiatives.

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“…The leading TBV candidates in clinical trials include Pfs230 [6][7][8][9][10][11][12][13][14][15][16][17][18][19] (NCT02942277, NCT05135273, and NCT02334462), Pfs25 [15,16,20] (NCT02942277, NCT00295581, NCT0186 7463, NCT02013687, NCT02532049, NCT02334462, NCT04130282, and NCT04271306), and Pfs48/45 [8,10,12,[21][22][23][24] (NCT05400746). Pfs230 [6][7][8][9]11] is a gametocyte surface protein that is part of the 6-cysteine protein family that includes the sexual stage proteins Pfs48/45, Pfs47, Pfs230p, Pfs36, and Pfs38 and the asexual stage proteins Pf41 and Pf12 [9,12,25].…”

Section: Introductionmentioning

confidence: 99%

A Self-Assembling Pfs230D1-Ferritin Nanoparticle Vaccine Has Potent and Durable Malaria Transmission-Reducing Activity

Salinas,

Ma,

McAleese

et al. 2024

Vaccines

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Malaria is caused by eukaryotic protozoan parasites of the genus Plasmodium. There are 249 million new cases and 608,000 deaths annually, and new interventions are desperately needed. Malaria vaccines can be divided into three categories: liver stage, blood stage, or transmission-blocking vaccines. Transmission-blocking vaccines prevent the transmission of disease by the mosquito vector from one human to another. Pfs230 is one of the leading transmission-blocking vaccine antigens for malaria. Here, we describe the development of a 24-copy self-assembling nanoparticle vaccine comprising domain 1 of Pfs230 genetically fused to H. pylori ferritin. The single-component Pfs230D1-ferritin construct forms a stable and homogenous 24-copy nanoparticle with good production yields. The nanoparticle is highly immunogenic, as two low-dose vaccinations of New Zealand White rabbits elicited a potent and durable antibody response with high transmission-reducing activity when formulated in two distinct adjuvants suitable for translation to human use. This single-component 24-copy Pfs230D1-ferritin nanoparticle vaccine has the potential to improve production pipelines and the cost of manufacturing a potent and durable transmission-blocking vaccine for malaria control.

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Potent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230

Cited by 16 publications

References 77 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

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

A Self-Assembling Pfs230D1-Ferritin Nanoparticle Vaccine Has Potent and Durable Malaria Transmission-Reducing Activity

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