Potent Transmission-blocking Monoclonal Antibodies from Naturally Exposed Individuals Target a Conserved Epitope on Plasmodium Falciparum Pfs230

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2023 Feb 15

PMID 36792575

Authors

Danton Ivanochko

Amanda Fabra-Garcia

Karina Teelen

Marga van de Vegte-Bolmer

Geert-Jan van Gemert

Jocelyn Newton

Anthony Semesi

Marloes de Bruijni

Judith Bolscher

Jordache Ramjith

Marta Szabat

Stefanie Vogt

Lucas Kraft

Sherie Duncan

Shwu-Maan Lee

Moses R Kamya

Margaret E Feeney

Prasanna Jagannathan

Bryan Greenhouse

Robert W Sauerwein

C Richter King

Randall S MacGill

Teun Bousema

Matthijs M Jore

Jean-Philippe Julien

Affiliations

Soon will be listed here.

Abstract

Pfs230 is essential for Plasmodium falciparum transmission to mosquitoes and is the protein targeted by the most advanced malaria-transmission-blocking vaccine candidate. Prior understanding of functional epitopes on Pfs230 is based on two monoclonal antibodies (mAbs) with moderate transmission-reducing activity (TRA), elicited from subunit immunization. Here, we screened the B cell repertoire of two naturally exposed individuals possessing serum TRA and identified five potent mAbs from sixteen Pfs230 domain-1-specific mAbs. Structures of three potent and three low-activity antibodies bound to Pfs230 domain 1 revealed four distinct epitopes. Highly potent mAbs from natural infection recognized a common conformational epitope that is highly conserved across P. falciparum field isolates, while antibodies with negligible TRA derived from natural infection or immunization recognized three distinct sites. Our study provides molecular blueprints describing P. falciparum TRA, informed by contrasting potent and non-functional epitopes elicited by natural exposure and vaccination.

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References

McLeod B, Miura K, Scally S, Bosch A, Nguyen N, Shin H . Potent antibody lineage against malaria transmission elicited by human vaccination with Pfs25. Nat Commun. 2019; 10(1):4328. PMC: 6760140. DOI: 10.1038/s41467-019-11980-6. View

Ayanful-Torgby R, Sarpong E, Abagna H, Donu D, Obboh E, Mensah B . Persistent Plasmodium falciparum infections enhance transmission-reducing immunity development. Sci Rep. 2021; 11(1):21380. PMC: 8560775. DOI: 10.1038/s41598-021-00973-5. View

Healy S, Anderson C, Swihart B, Mwakingwe A, Gabriel E, Decederfelt H . Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice. J Clin Invest. 2021; 131(7). PMC: 8011888. DOI: 10.1172/JCI146221. View

Adams P, Afonine P, Bunkoczi G, Chen V, Davis I, Echols N . PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 2):213-21. PMC: 2815670. DOI: 10.1107/S0907444909052925. View

Vermeulen A, Ponnudurai T, Beckers P, Verhave J, Smits M, Meuwissen J . Sequential expression of antigens on sexual stages of Plasmodium falciparum accessible to transmission-blocking antibodies in the mosquito. J Exp Med. 1985; 162(5):1460-76. PMC: 2187939. DOI: 10.1084/jem.162.5.1460. View

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

Moore P, Gray E, Wibmer C, Bhiman J, Nonyane M, Sheward D . Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape. Nat Med. 2012; 18(11):1688-92. PMC: 3494733. DOI: 10.1038/nm.2985. View

Kulp D, Steichen J, Pauthner M, Hu X, Schiffner T, Liguori A . Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding. Nat Commun. 2017; 8(1):1655. PMC: 5698488. DOI: 10.1038/s41467-017-01549-6. View

van der Boor S, Smit M, van Beek S, Ramjith J, Teelen K, van de Vegte-Bolmer M . Safety, tolerability, and Plasmodium falciparum transmission-reducing activity of monoclonal antibody TB31F: a single-centre, open-label, first-in-human, dose-escalation, phase 1 trial in healthy malaria-naive adults. Lancet Infect Dis. 2022; 22(11):1596-1605. PMC: 9605874. DOI: 10.1016/S1473-3099(22)00428-5. View

10.

Wrapp D, Wang N, Corbett K, Goldsmith J, Hsieh C, Abiona O . Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020; 367(6483):1260-1263. PMC: 7164637. DOI: 10.1126/science.abb2507. View

11.

Pallesen J, Wang N, Corbett K, Wrapp D, Kirchdoerfer R, Turner H . Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A. 2017; 114(35):E7348-E7357. PMC: 5584442. DOI: 10.1073/pnas.1707304114. View

12.

Stone W, Campo J, Ouedraogo A, Meerstein-Kessel L, Morlais I, Da D . Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity. Nat Commun. 2018; 9(1):558. PMC: 5805765. DOI: 10.1038/s41467-017-02646-2. View

13.

Xu J, McPartlon M, Li J . Improved protein structure prediction by deep learning irrespective of co-evolution information. Nat Mach Intell. 2021; 3:601-609. PMC: 8340610. DOI: 10.1038/s42256-021-00348-5. View

14.

Duffy P, Gorres J . Malaria vaccines since 2000: progress, priorities, products. NPJ Vaccines. 2020; 5(1):48. PMC: 7283239. DOI: 10.1038/s41541-020-0196-3. View

15.

de Jong R, Singh S, Teelen K, van de Vegte-Bolmer M, van Gemert G, Stone W . Heterologous Expression and Evaluation of Novel Transmission Blocking Vaccine Candidates. Front Immunol. 2022; 13:909060. PMC: 9259988. DOI: 10.3389/fimmu.2022.909060. View

16.

Rouge L, Chiang N, Steffek M, Kugel C, Croll T, Tam C . Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab. Science. 2020; 367(6483):1224-1230. DOI: 10.1126/science.aaz9356. View

17.

Datoo M, Natama M, Some A, Traore O, Rouamba T, Bellamy D . Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial. Lancet. 2021; 397(10287):1809-1818. PMC: 8121760. DOI: 10.1016/S0140-6736(21)00943-0. View

18.

Neafsey D, Juraska M, Bedford T, Benkeser D, Valim C, Griggs A . Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine. N Engl J Med. 2015; 373(21):2025-2037. PMC: 4762279. DOI: 10.1056/NEJMoa1505819. View

19.

Ringe R, Ozorowski G, Rantalainen K, Struwe W, Matthews K, Torres J . Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers. J Virol. 2017; 91(15). PMC: 5512241. DOI: 10.1128/JVI.00677-17. View

20.

Ponnudurai T, Lensen A, van Gemert G, Bensink M, Bolmer M, Meuwissen J . Infectivity of cultured Plasmodium falciparum gametocytes to mosquitoes. Parasitology. 1989; 98 Pt 2:165-73. DOI: 10.1017/s0031182000062065. View