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Structural and biophysical correlation of anti-NANP antibodies with in vivo protection against P. falciparum.

<div class='caption-title'>Assessment of antibody in vivo protection.</div>
<div class='caption-title'>Homotypic Fab–Fab interactions in Fab239- and Fab399-peptide complexes.</div>
<div class='caption-title'>Correlation of apparent affinity and dissociation constants with normalized parasite burden.</div>
Pholcharee T, Oyen D, Flores-Garcia Y, Gonzalez-Paez G, Han Z, Williams KL, Volkmuth W, Emerling D, Locke E, Richter King C, Zavala F, Wilson IA
OpenAccess logo Nat Commun 12 1063 (2021)
Related entries: 6w00, 6w05, 6wfw, 6wfx, 6wfy, 6wfz, 6wg0, 6wg1

Cited: 25 times
EuropePMC logo PMID: 33594061

Abstract

The most advanced P. falciparum circumsporozoite protein-based malaria vaccine, RTS,S/AS01 (RTS,S), confers partial protection but with antibody titers that wane relatively rapidly, highlighting the need to elicit more potent and durable antibody responses. Here, we elucidate crystal structures, binding affinities and kinetics, and in vivo protection of eight anti-NANP antibodies derived from an RTS,S phase 2a trial and encoded by three different heavy-chain germline genes. The structures reinforce the importance of homotypic Fab-Fab interactions in protective antibodies and the overwhelmingly dominant preference for a germline-encoded aromatic residue for recognition of the NANP motif. In this study, antibody apparent affinity correlates best with protection in an in vivo mouse model, with the more potent antibodies also recognizing epitopes with repeating secondary structural motifs of type I β- and Asn pseudo 310 turns; such insights can be incorporated into design of more effective immunogens and antibodies for passive immunization.

Reviews citing this publication (5)

  1. RTS,S: the first malaria vaccine. Zavala F. J Clin Invest 132 e156588 (2022)
  2. How to induce protective humoral immunity against Plasmodium falciparum circumsporozoite protein. Wahl I, Wardemann H. J Exp Med 219 e20201313 (2022)
  3. Malaria vaccines: a new era of prevention and control. Duffy PE, Gorres JP, Healy SA, Fried M. Nat Rev Microbiol (2024)
  4. Humoral Immune Responses to P. falciparum Circumsporozoite Protein (Pfcsp) Induced by the RTS, S Vaccine - Current Update. Ngulube P. Infect Drug Resist 16 2147-2157 (2023)
  5. Monoclonal antibodies to the circumsporozoite proteins as an emerging tool for malaria prevention. Wang LT, Idris AH, Kisalu NK, Crompton PD, Seder RA. Nat Immunol 25 1530-1545 (2024)

Articles citing this publication (20)

  1. Heterotypic interactions drive antibody synergy against a malaria vaccine candidate. Ragotte RJ, Pulido D, Lias AM, Quinkert D, Alanine DGW, Jamwal A, Davies H, Nacer A, Lowe ED, Grime GW, Illingworth JJ, Donat RF, Garman EF, Bowyer PW, Higgins MK, Draper SJ. Nat Commun 13 933 (2022)
  2. Functional human IgA targets a conserved site on malaria sporozoites. Tan J, Cho H, Pholcharee T, Pereira LS, Doumbo S, Doumtabe D, Flynn BJ, Schön A, Kanatani S, Aylor SO, Oyen D, Vistein R, Wang L, Dillon M, Skinner J, Peterson M, Li S, Idris AH, Molina-Cruz A, Zhao M, Olano LR, Lee PJ, Roth A, Sinnis P, Barillas-Mury C, Kayentao K, Ongoiba A, Francica JR, Traore B, Wilson IA, Seder RA, Crompton PD. Sci Transl Med 13 eabg2344 (2021)
  3. The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo. Flores-Garcia Y, Wang LT, Park M, Asady B, Idris AH, Kisalu NK, Muñoz C, Pereira LS, Francica JR, Seder RA, Zavala F. PLoS Pathog 17 e1010042 (2021)
  4. A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum. Beutler N, Pholcharee T, Oyen D, Flores-Garcia Y, MacGill RS, Garcia E, Calla J, Parren M, Yang L, Volkmuth W, Locke E, Regules JA, Dutta S, Emerling D, Early AM, Neafsey DE, Winzeler EA, King CR, Zavala F, Burton DR, Wilson IA, Rogers TF. PLoS Pathog 18 e1010409 (2022)
  5. Restricted valency (NPNA)n repeats and junctional epitope-based circumsporozoite protein vaccines against Plasmodium falciparum. Langowski MD, Khan FA, Savransky S, Brown DR, Balasubramaniyam A, Harrison WB, Zou X, Beck Z, Matyas GR, Regules JA, Miller R, Soisson LA, Batchelor AH, Dutta S. NPJ Vaccines 7 13 (2022)
  6. Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection. Martin GM, Torres JL, Pholcharee T, Oyen D, Flores-Garcia Y, Gibson G, Moskovitz R, Beutler N, Jung DD, Copps J, Lee WH, Gonzalez-Paez G, Emerling D, MacGill RS, Locke E, King CR, Zavala F, Wilson IA, Ward AB. Nat Commun 14 4546 (2023)
  7. The light chain of the L9 antibody is critical for binding circumsporozoite protein minor repeats and preventing malaria. Wang LT, Hurlburt NK, Schön A, Flynn BJ, Flores-Garcia Y, Pereira LS, Kiyuka PK, Dillon M, Bonilla B, Zavala F, Idris AH, Francica JR, Pancera M, Seder RA. Cell Rep 38 110367 (2022)
  8. Potent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230. Ivanochko D, Fabra-García A, Teelen K, van de Vegte-Bolmer M, van Gemert GJ, Newton J, Semesi A, de Bruijni M, Bolscher J, Ramjith J, Szabat M, Vogt S, Kraft L, Duncan S, Lee SM, Kamya MR, Feeney ME, Jagannathan P, Greenhouse B, Sauerwein RW, Richter King C, MacGill RS, Bousema T, Jore MM, Julien JP. Immunity 56 420-432.e7 (2023)
  9. A candidate antibody drug for prevention of malaria. Williams KL, Guerrero S, Flores-Garcia Y, Kim D, Williamson KS, Siska C, Smidt P, Jepson SZ, Li K, Dennison SM, Mathis-Torres S, Chen X, Wille-Reece U, MacGill RS, Walker M, Jongert E, King CR, Ockenhouse C, Glanville J, Moon JE, Regules JA, Tan YC, Cavet G, Lippow SM, Robinson WH, Dutta S, Tomaras GD, Zavala F, Ketchem RR, Emerling DE. Nat Med 30 117-129 (2024)
  10. High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire. Kucharska I, Binter Š, Murugan R, Scally SW, Ludwig J, Prieto K, Thai E, Costa G, Li K, Horn GQ, Flores-Garcia Y, Bosch A, Sicard T, Rubinstein JL, Zavala F, Dennison SM, Tomaras GD, Levashina EA, Kellam P, Wardemann H, Julien JP. PLoS Pathog 18 e1010999 (2022)
  11. Crystal structures of the human IgD Fab reveal insights into CH1 domain diversity. Davies AM, Beavil RL, Barbolov M, Sandhar BS, Gould HJ, Beavil AJ, Sutton BJ, McDonnell JM. Mol Immunol 159 28-37 (2023)
  12. Cytotoxicity of human antibodies targeting the circumsporozoite protein is amplified by 3D substrate and correlates with protection. Aguirre-Botero MC, Wang LT, Formaglio P, Aliprandini E, Thiberge JM, Schön A, Flores-Garcia Y, Mathis-Torres S, Flynn BJ, da Silva Pereira L, Le Duff Y, Hurley M, Nacer A, Bowyer PW, Zavala F, Idris AH, Francica JR, Seder RA, Amino R. Cell Rep 42 112681 (2023)
  13. Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats. Kucharska I, Hossain L, Ivanochko D, Yang Q, Rubinstein JL, Pomès R, Julien JP. Elife 11 e72908 (2022)
  14. Establishing RTS,S/AS01 as a benchmark for comparison to next-generation malaria vaccines in a mouse model. Locke E, Flores-Garcia Y, Mayer BT, MacGill RS, Borate B, Salgado-Jimenez B, Gerber MW, Mathis-Torres S, Shapiro S, King CR, Zavala F. NPJ Vaccines 9 29 (2024)
  15. Antibody dynamics in children with first or repeat Plasmodium falciparum infections. Rogier E, Nace D, Dimbu PR, Wakeman B, Beeson JG, Drakeley C, Tetteh K, Plucinski M. Front Med (Lausanne) 9 869028 (2022)
  16. Cryo-EM structures of anti-malarial antibody L9 with circumsporozoite protein reveal trimeric L9 association and complete 27-residue epitope. Tripathi P, Bender MF, Lei H, Da Silva Pereira L, Shen CH, Bonilla B, Dillon M, Ou L, Pancera M, Wang LT, Zhang B, Batista FD, Idris AH, Seder RA, Kwong PD. Structure 31 480-491.e4 (2023)
  17. Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein. Thai E, Murugan R, Binter Š, Burn Aschner C, Prieto K, Kassardjian A, Obraztsova AS, Kang RW, Flores-Garcia Y, Mathis-Torres S, Li K, Horn GQ, Huntwork RHC, Bolscher JM, de Bruijni MHC, Sauerwein R, Dennison SM, Tomaras GD, Zavala F, Kellam P, Wardemann H, Julien JP. Cell Rep 42 113330 (2023)
  18. Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9. Martin GM, Fernández-Quintero ML, Lee WH, Pholcharee T, Eshun-Wilson L, Liedl KR, Pancera M, Seder RA, Wilson IA, Ward AB. Nat Commun 14 2815 (2023)
  19. Novel antibody competition binding assay identifies distinct serological profiles associated with protection. Bolton JS, MacGill RS, Locke E, Regules JA, Bergmann-Leitner ES. Front Immunol 14 1303446 (2023)
  20. Comparative analyses of functional antibody-mediated inhibition with anti-circumsporozoite monoclonal antibodies against transgenic Plasmodium berghei. Nicholas J, Kolli SK, Subramani PA, De SL, Ogbondah MM, Barnes SJ, Ntumngia FB, Adams JH. Malar J 22 335 (2023)


Related citations provided by authors (1)

  1. Structural and biophysical correlation of anti-NANP antibodies with in vivo protection against P. falciparum. Pholcharee T, Oyen D, Flores-Garcia Y, Gonzalez-Paez G, Han Z, Williams KL, Volkmuth W, Emerling D, Locke E, King CR, Zavala F, Wilson IA Biorxiv - (2020)

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