Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5.
Malaria
Monoclonal Antibodies
PfRH5
Rational Vaccine Immunogen Design
Vaccines
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: Germany
ID NLM: 101487380
Informations de publication
Date de publication:
02 Sep 2024
02 Sep 2024
Historique:
received:
25
03
2024
accepted:
20
08
2024
revised:
20
08
2024
medline:
3
9
2024
pubmed:
3
9
2024
entrez:
2
9
2024
Statut:
aheadofprint
Résumé
There is an urgent need for improved malaria vaccine immunogens. Invasion of erythrocytes by Plasmodium falciparum is essential for its life cycle, preceding symptoms of disease and parasite transmission. Antibodies which target PfRH5 are highly effective at preventing erythrocyte invasion and the most potent growth-inhibitory antibodies bind a single epitope. Here we use structure-guided approaches to design a small synthetic immunogen, RH5-34EM which recapitulates this epitope. Structural biology and biophysics demonstrate that RH5-34EM is correctly folded and binds neutralising monoclonal antibodies with nanomolar affinity. In immunised rats, RH5-34EM induces PfRH5-targeting antibodies that inhibit parasite growth. While PfRH5-specific antibodies were induced at a lower concentration by RH5-34EM than by PfRH5, RH5-34EM induced antibodies that were a thousand-fold more growth-inhibitory as a factor of PfRH5-specific antibody concentration. Finally, we show that priming with RH5-34EM and boosting with PfRH5 achieves the best balance between antibody quality and quantity and induces the most effective growth-inhibitory response. This rationally designed vaccine immunogen is now available for use as part of future malaria vaccines, alone or in combination with other immunogens.
Identifiants
pubmed: 39223355
doi: 10.1038/s44321-024-00123-0
pii: 10.1038/s44321-024-00123-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust (WT)
ID : 220797/Z/20/Z
Organisme : Wellcome Trust (WT)
ID : 101020/Z/13/Z
Organisme : United States Agency for International Development (USAID)
ID : 7200AA20C00017
Informations de copyright
© 2024. The Author(s).
Références
Alanine DGW, Quinkert D, Kumarasingha R, Mehmood S, Donnellan FR, Minkah NK, Dadonaite B, Diouf A, Galaway F, Silk SE et al (2019) Human antibodies that slow erythrocyte invasion potentiate malaria-neutralizing antibodies. Cell 178:216–228.e221
doi: 10.1016/j.cell.2019.05.025
pubmed: 31204103
pmcid: 6602525
Azoitei ML, Correia BE, Ban YE, Carrico C, Kalyuzhniy O, Chen L, Schroeter A, Huang PS, McLellan JS, Kwong PD et al (2011) Computation-guided backbone grafting of a discontinuous motif onto a protein scaffold. Science 334:373–376
doi: 10.1126/science.1209368
pubmed: 22021856
Barrett JR, Pipini D, Wright ND, Cooper AJ, Gorini G, Quinkert D, Lias AM, Davies H, Rigby C, Aleshnick M et al (2024) Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype. Cell https://doi.org/10.1016/j.cell.2024.06.015
Baum J, Chen L, Healer J, Lopaticki S, Boyle M, Triglia T, Ehlgen F, Ralph SA, Beeson JG, Cowman AF (2009) Reticulocyte-binding protein homologue 5—an essential adhesin involved in invasion of human erythrocytes by Plasmodium falciparum. Int J Parasitol 39:371–380
doi: 10.1016/j.ijpara.2008.10.006
pubmed: 19000690
Beilsten-Edmands J, Winter G, Gildea R, Parkhurst J, Waterman D, Evans G (2020) Scaling diffraction data in the DIALS software package: algorithms and new approaches for multi-crystal scaling. Acta Crystallogr D Struct Biol 76:385–399
doi: 10.1107/S2059798320003198
pubmed: 32254063
pmcid: 7137103
Bricogne G, Blanc EBM, Flensburg C, Keller P, Paciorek W, Roversi PSA, Smart OS, Vonrhein C, Womack TO (2017) BUSTER version 2.10.4. Global Phasing Ltd, Cambridge, UK
Brune KD, Leneghan DB, Brian IJ, Ishizuka AS, Bachmann MF, Draper SJ, Biswas S, Howarth M (2016) Plug-and-display: decoration of virus-like particles via isopeptide bonds for modular immunization. Sci Rep 6:19234
doi: 10.1038/srep19234
pubmed: 26781591
pmcid: 4725971
Burton DR (2002) Antibodies, viruses and vaccines. Nat Rev Immunol 2:706–713
doi: 10.1038/nri891
pubmed: 12209139
Campeotto I, Goldenzweig A, Davey J, Barfod L, Marshall JM, Silk SE, Wright KE, Draper SJ, Higgins MK, Fleishman SJ (2017) One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen. Proc Natl Acad Sci USA 114:998–1002
doi: 10.1073/pnas.1616903114
pubmed: 28096331
pmcid: 5293100
Castro KM, Scheck A, Xiao S, Correia BE (2022) Computational design of vaccine immunogens. Curr Opin Biotechnol 78:102821
doi: 10.1016/j.copbio.2022.102821
pubmed: 36279815
Correia BE, Bates JT, Loomis RJ, Baneyx G, Carrico C, Jardine JG, Rupert P, Correnti C, Kalyuzhniy O, Vittal V et al (2014) Proof of principle for epitope-focused vaccine design. Nature 507:201–206
doi: 10.1038/nature12966
pubmed: 24499818
pmcid: 4260937
Crosnier C, Bustamante LY, Bartholdson SJ, Bei AK, Theron M, Uchikawa M, Mboup S, Ndir O, Kwiatkowski DP, Duraisingh MT et al (2011) Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature 480:534–537
doi: 10.1038/nature10606
pubmed: 22080952
pmcid: 3245779
Datoo MS, Natama MH, Some A, Traore O, Rouamba T, Bellamy D, Yameogo P, Valia D, Tegneri M, Ouedraogo F et al (2021) 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 397:1809–1818
doi: 10.1016/S0140-6736(21)00943-0
pubmed: 33964223
pmcid: 8121760
Douglas AD, Baldeviano GC, Lucas CM, Lugo-Roman LA, Crosnier C, Bartholdson SJ, Diouf A, Miura K, Lambert LE, Ventocilla JA et al (2015) A PfRH5-based vaccine is efficacious against heterologous strain blood-stage Plasmodium falciparum infection in aotus monkeys. Cell Host Microbe 17:130–139
doi: 10.1016/j.chom.2014.11.017
pubmed: 25590760
pmcid: 4297294
Douglas AD, Williams AR, Knuepfer E, Illingworth JJ, Furze JM, Crosnier C, Choudhary P, Bustamante LY, Zakutansky SE, Awuah DK et al (2014) Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5. J Immunol 192:245–258
doi: 10.4049/jimmunol.1302045
pubmed: 24293631
Draper SJ, Sack BK, King CR, Nielsen CM, Rayner JC, Higgins MK, Long CA, Seder RA (2018) Malaria vaccines: recent advances and new horizons. Cell Host Microbe 24:43–56
doi: 10.1016/j.chom.2018.06.008
pubmed: 30001524
pmcid: 6054918
Emsley P, Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60:2126–2132
doi: 10.1107/S0907444904019158
pubmed: 15572765
Evans PR, Murshudov GN (2013) How good are my data and what is the resolution? Acta Crystallogr D Biol Crystallogr 69:1204–1214
doi: 10.1107/S0907444913000061
pubmed: 23793146
pmcid: 3689523
Farrell B, Alam N, Hart MN, Jamwal A, Ragotte RJ, Walters-Morgan H, Draper SJ, Knuepfer E, Higgins MK (2024) The PfRCR complex bridges malaria parasite and erythrocyte during invasion. Nature 625:578–584
doi: 10.1038/s41586-023-06856-1
pubmed: 38123677
Gildea RJ, Beilsten-Edmands J, Axford D, Horrell S, Aller P, Sandy J, Sanchez-Weatherby J, Owen CD, Lukacik P, Strain-Damerell C et al (2022) xia2.multiplex: a multi-crystal data-analysis pipeline. Acta Crystallogr D Struct Biol 78:752–769
doi: 10.1107/S2059798322004399
pubmed: 35647922
pmcid: 9159281
Jamwal A, Constantin CF, Hirschi S, Henrich S, Bildl W, Fakler B, Draper SJ, Schulte U, Higgins MK (2023) Erythrocyte invasion-neutralising antibodies prevent Plasmodium falciparum RH5 from binding to basigin-containing membrane protein complexes. eLife 12:e83681
doi: 10.7554/eLife.83681
pubmed: 37796723
pmcid: 10569788
Jin J, Tarrant RD, Bolam EJ, Angell-Manning P, Soegaard M, Pattinson DJ, Dulal P, Silk SE, Marshall JM, Dabbs RA et al (2018) Production, quality control, stability, and potency of cGMP-produced Plasmodium falciparum RH5.1 protein vaccine expressed in Drosophila S2 cells. NPJ Vaccines 3:32
doi: 10.1038/s41541-018-0071-7
pubmed: 30131879
pmcid: 6098134
King LDW, Pulido D, Barrett JR, Davies H, Quinkert D, Lias AM, Silk SE, Pattinson DJ, Diouf A, Williams BG, McHugh K, Rodrigues A, Rigby CA, Strazza V, Suurbaar J, Rees-Spear C, Dabbs RA, Ishizuka AS, Zhou Y, Gupta G, Jin J, Li Y, Carnrot C, Minassian AM, Campeotto I, Fleishman SJ, Noe AR, MacGill RS, King CR, Birkett AJ, Soisson LA, Long CA, Miura K, Ashfield R, Skinner K, Howarth MR, Biswas S, Draper SJ (2024) Preclinical development of a stabilized RH5 virus-like particle vaccine that induces improved antimalarial antibodies. Cell Rep Med 5(7):101654
Leman JK, Weitzner BD, Lewis SM, Adolf-Bryfogle J, Alam N, Alford RF, Aprahamian M, Baker D, Barlow KA, Barth P et al (2020) Macromolecular modeling and design in Rosetta: recent methods and frameworks. Nat Methods 17:665–680
doi: 10.1038/s41592-020-0848-2
pubmed: 32483333
Liebschner D, Afonine PV, Baker ML, Bunkoczi G, Chen VB, Croll TI, Hintze B, Hung LW, Jain S, McCoy AJ et al (2019) Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr D Struct Biol 75:861–877
doi: 10.1107/S2059798319011471
pubmed: 31588918
pmcid: 6778852
Marini A, Zhou Y, Li Y, Taylor IJ, Leneghan DB, Jin J, Zaric M, Mekhaiel D, Long CA, Miura K et al (2019) A universal plug-and-display vaccine carrier based on HBsAg VLP to maximize effective antibody response. Front Immunol 10:2931
doi: 10.3389/fimmu.2019.02931
pubmed: 31921185
pmcid: 6921968
McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ (2007) Phaser crystallographic software. J Appl Crystallogr 40:658–674
doi: 10.1107/S0021889807021206
pubmed: 19461840
pmcid: 2483472
McLellan JS, Correia BE, Chen M, Yang Y, Graham BS, Schief WR, Kwong PD (2011) Design and characterization of epitope-scaffold immunogens that present the motavizumab epitope from respiratory syncytial virus. J Mol Biol 409:853–866
doi: 10.1016/j.jmb.2011.04.044
pubmed: 21549714
pmcid: 3107930
McNamara HA, Idris AH, Sutton HJ, Vistein R, Flynn BJ, Cai Y, Wiehe K, Lyke KE, Chatterjee D, Kc N et al (2020) Antibody feedback limits the expansion of B cell responses to malaria vaccination but drives diversification of the humoral response. Cell Host Microbe 28:572–585.e577
doi: 10.1016/j.chom.2020.07.001
pubmed: 32697938
Minassian AM, Silk SE, Barrett JR, Nielsen CM, Miura K, Diouf A, Loos C, Fallon JK, Michell AR, White MT et al (2021) Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination. Med (NY) 2:701–719.e719
World Health Organisation (2022) World Malaria Report
Ragotte RJ, Pulido D, Lias AM, Quinkert D, Alanine DGW, Jamwal A, Davies H, Nacer A, Lowe ED, Grime GW et al (2022) Heterotypic interactions drive antibody synergy against a malaria vaccine candidate. Nat Commun 13:933
doi: 10.1038/s41467-022-28601-4
pubmed: 35177602
pmcid: 8854392
Scally SW, Triglia T, Evelyn C, Seager BA, Pasternak M, Lim PS, Healer J, Geoghegan ND, Adair A, Tham WH et al (2022) PCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum. Nat Microbiol 7:2039–2053
doi: 10.1038/s41564-022-01261-2
pubmed: 36396942
pmcid: 9712106
Schoeder CT, Gilchuk P, Sangha AK, Ledwitch KV, Malherbe DC, Zhang X, Binshtein E, Williamson LE, Martina CE, Dong J et al (2022) Epitope-focused immunogen design based on the ebolavirus glycoprotein HR2-MPER region. PLoS Pathog 18:e1010518
doi: 10.1371/journal.ppat.1010518
pubmed: 35584193
pmcid: 9170092
Schoeder CT, Schmitz S, Adolf-Bryfogle J, Sevy AM, Finn JA, Sauer MF, Bozhanova NG, Mueller BK, Sangha AK, Bonet J et al (2021) Modeling immunity with Rosetta: methods for antibody and antigen design. Biochemistry 60:825–846
doi: 10.1021/acs.biochem.0c00912
pubmed: 33705117
Sesterhenn F, Bonet J, Correia BE (2018) Structure-based immunogen design-leading the way to the new age of precision vaccines. Curr Opin Struct Biol 51:163–169
doi: 10.1016/j.sbi.2018.06.002
pubmed: 29980105
pmcid: 7127059
Sesterhenn F, Galloux M, Vollers SS, Csepregi L, Yang C, Descamps D, Bonet J, Friedensohn S, Gainza P, Corthesy P et al (2019) Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen. PLoS Biol 17:e3000164
doi: 10.1371/journal.pbio.3000164
pubmed: 30789898
pmcid: 6400402
Sesterhenn F, Yang C, Bonet J, Cramer JT, Wen X, Wang Y, Chiang CI, Abriata LA, Kucharska I, Castoro G et al (2020) De novo protein design enables the precise induction of RSV-neutralizing antibodies. Science 368:eaay5051
doi: 10.1126/science.aay5051
pubmed: 32409444
pmcid: 7391827
Silk SE, Kalinga WF, Salkeld J, Mtaka IM, Ahmed S, Milando F, Diouf A, Bundi CK, Balige N, Hassan O et al (2024) Blood-stage malaria vaccine candidate RH5.1/Matrix-M in healthy Tanzanian adults and children; an open-label, non-randomised, first-in-human, single-centre, phase 1b trial. Lancet Infect Dis https://doi.org/10.1016/S1473-3099(24)00312-8
Stertman L, Palm AE, Zarnegar B, Carow B, Lunderius Andersson C, Magnusson SE, Carnrot C, Shinde V, Smith G, Glenn G et al (2023) The Matrix-M adjuvant: A critical component of vaccines for the 21(st) century. Hum Vaccin Immunother 19:2189885
doi: 10.1080/21645515.2023.2189885
pubmed: 37113023
pmcid: 10158541
Volz JC, Yap A, Sisquella X, Thompson JK, Lim NT, Whitehead LW, Chen L, Lampe M, Tham WH, Wilson D et al (2016) Essential role of the PfRh5/PfRipr/CyRPA complex during Plasmodium falciparum invasion of erythrocytes. Cell Host Microbe 20:60–71
doi: 10.1016/j.chom.2016.06.004
pubmed: 27374406
Wang LT, Cooper AJ, Farrell B, Miura K, Diouf A, Muller-Sienerth N, Crosnier C, Purser L, Maciuszek M, Barrett JR et al (2024) Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5. Cell https://doi.org/10.1016/j.cell.2024.06.037
Williams BG, King LDW, Pulido D, Quinkert D, Lias AM, Silk SE, Ragotte RJ, Davies H, Barrett JR, McHugh K et al (2024) Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex. Nat Commun 15:4857
doi: 10.1038/s41467-024-48721-3
pubmed: 38849365
pmcid: 11161584
Wright KE, Hjerrild KA, Bartlett J, Douglas AD, Jin J, Brown RE, Illingworth JJ, Ashfield R, Clemmensen SB, de Jongh WA et al (2014) Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies. Nature 515:427–430
doi: 10.1038/nature13715
pubmed: 25132548
pmcid: 4240730
Zavala F (2022) RTS,S: the first malaria vaccine. J Clin Investig 132:e156588
doi: 10.1172/JCI156588
pubmed: 34981788
pmcid: 8718142
Zenonos ZA, Dummler SK, Muller-Sienerth N, Chen J, Preiser PR, Rayner JC, Wright GJ (2015) Basigin is a druggable target for host-oriented antimalarial interventions. J Exp Med 212:1145–1151
doi: 10.1084/jem.20150032
pubmed: 26195724
pmcid: 4516795