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

Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):E10438-E10445. doi: 10.1073/pnas.1715812114. Epub 2017 Nov 14.


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.

Trial registration: NCT01857869.

Keywords: EM; X-ray crystallography; antibodies; circumsporozoite protein; malaria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Protozoan / chemistry
  • Antibodies, Protozoan / immunology*
  • Antigens, Protozoan / chemistry
  • Antigens, Protozoan / immunology*
  • Antigens, Protozoan / isolation & purification
  • Antigens, Protozoan / therapeutic use
  • Clinical Trials, Phase II as Topic
  • Crystallography, X-Ray
  • Epitope Mapping
  • Epitopes / chemistry
  • Epitopes / immunology
  • Humans
  • Malaria Vaccines / chemistry
  • Malaria Vaccines / immunology*
  • Malaria Vaccines / therapeutic use
  • Malaria, Falciparum / immunology
  • Malaria, Falciparum / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Plasmodium falciparum / immunology*
  • Plasmodium falciparum / metabolism
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / immunology*
  • Protozoan Proteins / isolation & purification
  • Protozoan Proteins / therapeutic use
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / immunology
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / therapeutic use
  • Repetitive Sequences, Amino Acid / immunology
  • Structure-Activity Relationship


  • Antibodies, Protozoan
  • Antigens, Protozoan
  • Epitopes
  • Malaria Vaccines
  • Protozoan Proteins
  • Recombinant Proteins
  • circumsporozoite protein, Protozoan

Associated data

  • PDB/6AXK
  • PDB/6AXL