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

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 in this paper, 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. Lastly, together, these structural insights may aid in themore » design of a next-generation malaria vaccine.« less
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [3] ;  [4] ;  [3] ;  [5] ;  [5] ;  [1] ;  [2] ;  [6]
  1. Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology
  2. PATH Center for Vaccine Innovation and Access, Washington, DC (United States). PATH's Malaria Vaccine Initiative
  3. Atreca Inc., Redwood City, CA (United States)
  4. Stanford Univ., CA (United States). Dept. of Microbiology and Immunology
  5. Johns Hopkins Univ., Baltimore, MD (United States). Bloomberg School of Public Health, Malaria Research Inst.
  6. Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology; Scripps Research Inst., La Jolla, CA (United States). Skaggs Inst. for Chemical Biology
Publication Date:
Grant/Contract Number:
AC02-76SF00515; AI44375; P41GM103393; AC02-06CH11357; 1S10OD012289-01A1
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 48; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; malaria; circumsporozoite protein; antibodies; X-ray crystallography; EM
OSTI Identifier:
1423464

Oyen, David, Torres, Jonathan L., Wille-Reece, Ulrike, Ockenhouse, Christian F., Emerling, Daniel, Glanville, Jacob, Volkmuth, Wayne, Flores-Garcia, Yevel, Zavala, Fidel, Ward, Andrew B., King, C. Richter, and Wilson, Ian A.. Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein. United States: N. p., Web. doi:10.1073/pnas.1715812114.
Oyen, David, Torres, Jonathan L., Wille-Reece, Ulrike, Ockenhouse, Christian F., Emerling, Daniel, Glanville, Jacob, Volkmuth, Wayne, Flores-Garcia, Yevel, Zavala, Fidel, Ward, Andrew B., King, C. Richter, & Wilson, Ian A.. Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein. United States. doi:10.1073/pnas.1715812114.
Oyen, David, Torres, Jonathan L., Wille-Reece, Ulrike, Ockenhouse, Christian F., Emerling, Daniel, Glanville, Jacob, Volkmuth, Wayne, Flores-Garcia, Yevel, Zavala, Fidel, Ward, Andrew B., King, C. Richter, and Wilson, Ian A.. 2017. "Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein". United States. doi:10.1073/pnas.1715812114. https://www.osti.gov/servlets/purl/1423464.
@article{osti_1423464,
title = {Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein},
author = {Oyen, David and Torres, Jonathan L. and Wille-Reece, Ulrike and Ockenhouse, Christian F. and Emerling, Daniel and Glanville, Jacob and Volkmuth, Wayne and Flores-Garcia, Yevel and Zavala, Fidel and Ward, Andrew B. and King, C. Richter and Wilson, Ian A.},
abstractNote = {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 in this paper, 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. Lastly, together, these structural insights may aid in the design of a next-generation malaria vaccine.},
doi = {10.1073/pnas.1715812114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 48,
volume = 114,
place = {United States},
year = {2017},
month = {11}
}

Works referenced in this record:

RELION: Implementation of a Bayesian approach to cryo-EM structure determination
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PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
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