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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [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

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.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-76SF00515; AC02-06CH11357
OSTI ID:
1423464
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 48 Vol. 114; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
English

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  • Libraries, The University of North Carolina at Chapel Hill University
  • The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/nw7n-rk58
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Novel Strategies for Malaria Vaccine Design journal November 2018
Qualified Biolayer Interferometry Avidity Measurements Distinguish the Heterogeneity of Antibody Interactions with Plasmodium falciparum Circumsporozoite Protein Antigens journal July 2018
Identification and Characterization of Functional Human Monoclonal Antibodies to Plasmodium vivax Duffy-Binding Protein journal April 2019