Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses

McLeod, Brandon; Mabrouk, Moustafa T.; Miura, Kazutoyo; Ravichandran, Rashmi; Kephart, Sally; Hailemariam, Sophia; Pham, Thao; Semesi, A.; Kucharska, Iga; Kundu, Prasun; Huang, Wei‐Chiao; Johnson, Max; Blackstone, Alyssa; Pettie, Deleah; Murphy, Michael; Kraft, John C.; Leaf, Elizabeth M.; Yang, Jing; Vegte‐Bolmer, Marga van de; Gemert, Geert-Jan van; Ramjith, Jordache; King, C. Richter; MacGill, Randall S.; Wu, Yimin; Lee, Kelly K.; Jore, Matthijs M.; King, Neil P.; Lovell, Jonathan F.; Julien, Jean-Philippe

doi:10.1016/j.immuni.2022.07.015

Cited by 37 publications

(25 citation statements)

References 60 publications

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“…Using X-ray crystallography, we next uncovered the epitopes of non-TB31F-competing, potent antibodies RUPA-44 and RUPA-117 ( Figures 5 A, 5B, and S4 A–S4D; Table S3 , PDB: 7UNB). 29 RUPA-44 and RUPA-117 have almost identical sequences, with just two amino acid substitutions in the light chain and four in the heavy chain ( Figure S5 E). As a result, they bind to very similar epitopes and share the majority of contacts.…”

Section: Resultsmentioning

confidence: 99%

“… 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 …”

Section: Resultsmentioning

confidence: 99%

“… 21 N/A Chemicals, peptides, and recombinant proteins Pfs48/45 6C.mAgE1 McLeod et al. 29 N/A Pfs48/45 6C.mAgE1 (K416N; C terminal 6x HIS tag) This paper N/A Pfs48/45 6C.mAgE1 (S322N; C terminal 6x HIS tag) This paper N/A Pfs48/45 6C.mAgE1 (D320H; C terminal 6x HIS tag) This paper N/A Pfs48/45 6C.mAgE1 (L314I; C terminal 6x HIS tag) This paper N/A GIBCO™ FreeStyle™ 293 Expression Medium Thermo Fisher Scientific Cat#12338026 FectoPRO DNA Transfection Reagent VWR Cat#10118-444 Pfs48/45 R0.6C Singh et al. 16 N/A Pfs48/45 full length This paper N/A Pfs48/45 D1-2 (N28-K289) This paper N/A Pfs48/45 D2-3 (H184-A428) This paper N/A Pfs48/45 D3 (K287-A428) This paper N/A DyLight™ 594 NHS Ester Thermo Fisher Cat#46413 DyLight™ 755 NHS Ester Thermo Fisher Cat#62279 Pierce IgG elution buffer Thermo Fisher Cat#21004 10X HBSTE running buffer Carterra Cat#3630 0.1 M MES Carterra Cat#3625 10 mM sodium acetate buffer Carterra Cat#3801 10 mM glycine pH 2.0 Carterra Cat#3640 Sulfo–N-hydroxysuccinimide (sulfo-NHS) Thermo Fisher Cat#24510 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) Thermo Fisher Cat#22980 …”

Section: Methodsmentioning

confidence: 99%

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

Fabra-García¹,

Hailemariam²,

Jong³

et al. 2023

Immunity

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Fabra-García¹,

Hailemariam²,

Jong³

et al. 2023

Immunity

Self Cite

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“…The numerous benefits of a non-glycosylated antigen described above are some of the aspects that distinguish these SPEEDesign immunogens from another recently reported stabilized Pfs48/45-D3 nanoparticle 53 . Mcleod et al created thermostabilized immunogens that could be displayed on nanoparticles and similarly elicited TRA much greater than WT D3, supporting the notion that antigen stabilization is a powerful method to improve vaccine efficacy.…”

Section: Discussionmentioning

confidence: 95%

Design of a stabilized non-glycosylated Pfs48/45 antigen enables a potent malaria transmission-blocking nanoparticle vaccine

et al. 2023

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A malaria vaccine that blocks parasite transmission from human to mosquito would be a powerful method of disrupting the parasite lifecycle and reducing the incidence of disease in humans. Pfs48/45 is a promising antigen in development as a transmission blocking vaccine (TBV) against the deadliest malaria parasite Plasmodium falciparum. The third domain of Pfs48/45 (D3) is an established TBV candidate, but production challenges have hampered development. For example, to date, a non-native N-glycan is required to stabilize the domain when produced in eukaryotic systems. Here, we implement a SPEEDesign computational design and in vitro screening pipeline that retains the potent transmission blocking epitope in Pfs48/45 while creating a stabilized non-glycosylated Pfs48/45 D3 antigen with improved characteristics for vaccine manufacture. This antigen can be genetically fused to a self-assembling single-component nanoparticle, resulting in a vaccine that elicits potent transmission-reducing activity in rodents at low doses. The enhanced Pfs48/45 antigen enables many new and powerful approaches to TBV development, and this antigen design method can be broadly applied towards the design of other vaccine antigens and therapeutics without interfering glycans.

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“…In a recent study, bioinformatics approaches has been used to design nanoparticle-based, stabilized Pf s48/45 vaccines which were then administered in mice model. These multimeric Pf s48/45-6C vaccines elicited antibodies that drive potent transmission-reducing activity ( 149 ). P. falciparum protein, P47 is a paralog of Pf s48/45.…”

Section: Vaccine Candidates Against Plasmodiummentioning

confidence: 99%

Host-parasite interactions during Plasmodium infection: Implications for immunotherapies

et al. 2023

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Malaria is a global infectious disease that remains a leading cause of morbidity and mortality in the developing world. Multiple environmental and host and parasite factors govern the clinical outcomes of malaria. The host immune response against the Plasmodium parasite is heterogenous and stage-specific both in the human host and mosquito vector. The Plasmodium parasite virulence is predominantly associated with its ability to evade the host’s immune response. Despite the availability of drug-based therapies, Plasmodium parasites can acquire drug resistance due to high antigenic variations and allelic polymorphisms. The lack of licensed vaccines against Plasmodium infection necessitates the development of effective, safe and successful therapeutics. To design an effective vaccine, it is important to study the immune evasion strategies and stage-specific Plasmodium proteins, which are targets of the host immune response. This review provides an overview of the host immune defense mechanisms and parasite immune evasion strategies during Plasmodium infection. Furthermore, we also summarize and discuss the current progress in various anti-malarial vaccine approaches, along with antibody-based therapy involving monoclonal antibodies, and research advancements in host-directed therapy, which can together open new avenues for developing novel immunotherapies against malaria infection and transmission.

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Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses

Cited by 37 publications

References 60 publications

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

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

Design of a stabilized non-glycosylated Pfs48/45 antigen enables a potent malaria transmission-blocking nanoparticle vaccine

Host-parasite interactions during Plasmodium infection: Implications for immunotherapies

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