Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein

David Oyen, Jonathan L. Torres, Ulrike Wille-Reece, Christian F. Ockenhouse, Daniel Emerling, Jacob Glanville, Wayne Volkmuth, Yevel Flores-Garcia, Fidel Zavala, Andrew B. Ward, C. Richter King, Ian A. Wilson

Research output: Contribution to journalArticle

Abstract

Acquired resistance against antimalarial drugs has further increased the need for an effective malaria vaccine. The current leading candidate, RTS,S, is a recombinant circumsporozoite protein (CSP)-based vaccine against Plasmodium falciparum that contains 19 NANP repeats followed by a thrombospondin repeat domain. Although RTS,S has undergone extensive clinical testing and has progressed through phase III clinical trials, continued efforts are underway to enhance its efficacy and duration of protection. Here, we determined that two monoclonal antibodies (mAbs 311 and 317), isolated from a recent controlled human malaria infection trial exploring a delayed fractional dose, inhibit parasite development in vivo by at least 97%. Crystal structures of antibody fragments (Fabs) 311 and 317 with an (NPNA)3 peptide illustrate their different binding modes. Notwithstanding, one and three of the three NPNA repeats adopt similar well-defined type I β-turns with Fab311 and Fab317, respectively. Furthermore, to explore antibody binding in the context of P. falciparum CSP, we used negative-stain electron microscopy on a recombinant shortened CSP (rsCSP) construct saturated with Fabs. Both complexes display a compact rsCSP with multiple Fabs bound, with the rsCSP–Fab311 complex forming a highly organized helical structure. Together, these structural insights may aid in the design of a next-generation malaria vaccine.

Original languageEnglish (US)
Pages (from-to)E10438-E10445
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number48
DOIs
StatePublished - Nov 28 2017

Keywords

  • Antibodies
  • Circumsporozoite protein
  • EM
  • Malaria
  • X-ray crystallography

ASJC Scopus subject areas

  • General

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    Oyen, D., Torres, J. L., Wille-Reece, U., Ockenhouse, C. F., Emerling, D., Glanville, J., Volkmuth, W., Flores-Garcia, Y., Zavala, F., Ward, A. B., Richter King, C., & Wilson, I. A. (2017). Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein. Proceedings of the National Academy of Sciences of the United States of America, 114(48), E10438-E10445. https://doi.org/10.1073/pnas.1715812114