TY - JOUR
T1 - Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein
AU - Oyen, David
AU - Torres, Jonathan L.
AU - Wille-Reece, Ulrike
AU - Ockenhouse, Christian F.
AU - Emerling, Daniel
AU - Glanville, Jacob
AU - Volkmuth, Wayne
AU - Flores-Garcia, Yevel
AU - Zavala, Fidel
AU - Ward, Andrew B.
AU - Richter King, C.
AU - Wilson, Ian A.
N1 - Funding Information:
We thank Erik Jongert and Constantinos Kurt Wibmer for critical reading of the manuscript and Robyn L. Stanfield for technical expertise. This work was funded by PATH’s Malaria Vaccine Initiative under a collaborative agreement with The Scripps Research Institute. The work reported here is dependent on a more comprehensive analysis of antibodies elicited in a CHMI study conducted by a partnership of Walter Reed Army Institute of Research, GlaxoSmithKline Biologicals SA, Atreca Inc., and PATH’s Malaria Vaccine Initiative. The CHMI trial is registered with Clinical-Trials.gov, no. NCT01857869. The SSRL, SLAC National Accelerator Laboratory, is supported by the US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by NIH National Institute of General Medical Sciences (NIGMS), including Grant P41GM103393. GM/CA @ APS is funded in whole or in part by National Cancer Institute Grant ACB-12002 and NIGMS Grant AGM-12006. This research used the resources of the APS, a US DOE Office of Science User Facility operated by Argonne National Laboratory under Contract DE-AC02-06CH11357. The Eiger 16M detector was funded by NIH Office of Research Infrastructure Programs, High-End Instrumentation Grant 1S10OD012289-01A1. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the DOE, NIGMS, or NIH.
Funding Information:
ACKNOWLEDGMENTS. We thank Erik Jongert and Constantinos Kurt Wibmer for critical reading of the manuscript and Robyn L. Stanfield for technical expertise. This work was funded by PATH’s Malaria Vaccine Initiative under a collaborative agreement with The Scripps Research Institute. The work reported here is dependent on a more comprehensive analysis of antibodies elicited in a CHMI study conducted by a partnership of Walter Reed Army Institute of Research, GlaxoSmithKline Biologicals SA, Atreca Inc., and PATH’s Malaria Vaccine Initiative. The CHMI trial is registered with Clinical-Trials.gov, no. NCT01857869. The SSRL, SLAC National Accelerator Laboratory, is supported by the US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by NIH National Institute of General Medical Sciences (NIGMS), including Grant P41GM103393. GM/CA @ APS is funded in whole or in part by National Cancer Institute Grant ACB-12002 and NIGMS Grant AGM-12006. This research used the resources of the APS, a US DOE Office of Science User Facility operated by Argonne National Laboratory under Contract DE-AC02-06CH11357. The Eiger 16M detector was funded by NIH Office of Research Infrastructure Programs, High-End Instrumentation Grant 1S10OD012289-01A1. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the DOE, NIGMS, or NIH.
Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.
PY - 2017/11/28
Y1 - 2017/11/28
N2 - 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.
AB - 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.
KW - Antibodies
KW - Circumsporozoite protein
KW - EM
KW - Malaria
KW - X-ray crystallography
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U2 - 10.1073/pnas.1715812114
DO - 10.1073/pnas.1715812114
M3 - Article
C2 - 29138320
AN - SCOPUS:85035244222
SN - 0027-8424
VL - 114
SP - E10438-E10445
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 48
ER -