@article{3e0a36dfc04a4b8d8703b5b422d9ed9c,
title = "Natural Parasite Exposure Induces Protective Human Anti-Malarial Antibodies",
abstract = "Antibodies against the NANP repeat of circumsporozoite protein (CSP), the major surface antigen of Plasmodium falciparum (Pf) sporozoites, can protect from malaria in animal models but protective humoral immunity is difficult to induce in humans. Here we cloned and characterized rare affinity-matured human NANP-reactive memory B cell antibodies elicited by natural Pf exposure that potently inhibited parasite transmission and development in vivo. We unveiled the molecular details of antibody binding to two distinct protective epitopes within the NANP repeat. NANP repeat recognition was largely mediated by germline encoded and immunoglobulin (Ig) heavy-chain complementarity determining region 3 (HCDR3) residues, whereas affinity maturation contributed predominantly to stabilizing the antigen-binding site conformation. Combined, our findings illustrate the power of exploring human anti-CSP antibody responses to develop tools for malaria control in the mammalian and the mosquito vector and provide a molecular basis for the structure-based design of next-generation CSP malaria vaccines. CSP is the target of protective antibodies against the malaria parasite Plasmodium falciparum (Pf). Here, Triller and Scally et al. identified potent Pf-inhibitory human anti-CSP memory B cell antibodies induced by natural exposure and unveiled the molecular details of antigen binding to two protective CSP repeat epitopes.",
keywords = "Plasmodium falciparum, X-ray structures, affinity maturation, circumsporozoite protein, epitope specificity, human, malaria, memory B cells, natural infection, protective antibodies",
author = "Gianna Triller and Scally, {Stephen W.} and Giulia Costa and Maria Pissarev and Cornelia Kreschel and Alexandre Bosch and Eric Marois and Sack, {Brandon K.} and Rajagopal Murugan and Salman, {Ahmed M.} and Janse, {Chris J.} and Khan, {Shahid M.} and Kappe, {Stefan H.I.} and Adegnika, {Ayola A.} and Benjamin Mordm{\"u}ller and Levashina, {Elena A.} and Julien, {Jean Philippe} and Hedda Wardemann",
note = "Funding Information: The authors are grateful to all study participants and thank P.G. Kremsner, B. Lell, M. Massinga Loemb{\'e}, E. Askani, and members of the Albert Schweitzer Hospital and CERMEL for their support. Further, they thank Christian Busse (German Cancer Research Center, Heidelberg), Peter Sehr (EMBL-DKFZ Chemical Biology Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany), Hanne Kr{\"u}ger, Dana Tschierske, Liane Spohr, Daniel Eyermann, and Manuela Andres (MPIIB, Berlin) for technical assistance. G.T. was supported by the International Max Planck Research School for Infectious Diseases and Immunology (IMPRS-IDI) and the German National Academic Foundation. X-ray diffraction experiments were performed using beamline 08ID-1 at the Canadian Light Source, which is supported by the Canada Foundation for Innovation, Natural Sciences and Engineering Research Council of Canada, the University of Saskatchewan, the Government of Saskatchewan, Western Economic Diversification Canada, the National Research Council Canada, and the Canadian Institutes of Health Research (CIHR). SAXS experiments were performed at beamline 18-ID of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Part of this work was funded by NIH grant # F32 AI 114113 and by CNRS in the frame of the LIA “ REL2 and resistance to malaria ”. The following reagents were obtained through BEI Resources, NIAID, NIH: Hybridoma 2A10 Anti-Plasmodium falciparum Circumsporozoite Protein (CSP), MRA-183, contributed by Elizabeth Nardin and HC-04, Hepatocyte (human), MRA-975, contributed by Jetsumon Sattabongkot Prachumsri. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = dec,
day = "19",
doi = "10.1016/j.immuni.2017.11.007",
language = "English (US)",
volume = "47",
pages = "1197--1209.e10",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "6",
}