Natural Parasite Exposure Induces Protective Human Anti-Malarial Antibodies

Gianna Triller; Stephen W Scally; Giulia Costa; Maria Pissarev; Cornelia Kreschel; Alexandre Bosch; Eric Marois; Brandon K Sack; Rajagopal Murugan; Ahmed M Salman; Chris J Janse; Shahid M Khan; Stefan H I Kappe; Ayola A Adegnika; Benjamin Mordmüller; Elena A Levashina; Jean-Philippe Julien; Hedda Wardemann

doi:10.1016/j.immuni.2017.11.007

Natural Parasite Exposure Induces Protective Human Anti-Malarial Antibodies

Immunity. 2017 Dec 19;47(6):1197-1209.e10. doi: 10.1016/j.immuni.2017.11.007. Epub 2017 Nov 29.

Authors

Gianna Triller¹, Stephen W Scally², Giulia Costa³, Maria Pissarev³, Cornelia Kreschel³, Alexandre Bosch², Eric Marois⁴, Brandon K Sack⁵, Rajagopal Murugan¹, Ahmed M Salman⁶, Chris J Janse⁷, Shahid M Khan⁷, Stefan H I Kappe⁵, Ayola A Adegnika⁸, Benjamin Mordmüller⁹, Elena A Levashina³, Jean-Philippe Julien¹⁰, Hedda Wardemann¹¹

Affiliations

¹ B Cell Immunology, German Cancer Research Center, Heidelberg, 69120, Germany.
² Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada.
³ Vector Biology Unit, Max Planck Institute for Infection Biology, Berlin, 10117, Germany.
⁴ UPR9022 CNRS, U963 Inserm, Université de Strasbourg, Strasbourg, 67000, France.
⁵ Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
⁶ The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK; Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
⁷ Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
⁸ Centre de Recherches Médicales de Lambaréné, Lambaréné, 242, Gabon; Institute of Tropical Medicine and German Center for Infection Research, partner site Tübingen, University of Tübingen, Tübingen, 72074, Germany; Leiden University Medical Centre (LUMC), Leiden, 2333 ZA, The Netherlands.
⁹ Institute of Tropical Medicine and German Center for Infection Research, partner site Tübingen, University of Tübingen, Tübingen, 72074, Germany.
¹⁰ Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; Departments of Biochemistry and Immunology, University of Toronto, ON M5G 0A4, Canada. Electronic address: [email protected].
¹¹ B Cell Immunology, German Cancer Research Center, Heidelberg, 69120, Germany. Electronic address: [email protected].

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.

Keywords: Plasmodium falciparum; X-ray structures; affinity maturation; circumsporozoite protein; epitope specificity; human; malaria; memory B cells; natural infection; protective antibodies.

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 / biosynthesis
Antibodies, Protozoan / chemistry
Antibodies, Protozoan / immunology*
Antigens, Protozoan / chemistry
Antigens, Protozoan / genetics
Antigens, Protozoan / immunology*
B-Lymphocytes / immunology
B-Lymphocytes / parasitology
Crystallography, X-Ray
Epitopes / chemistry
Epitopes / immunology
Female
Gene Expression
Humans
Immunity, Humoral*
Immunoglobulin Heavy Chains / biosynthesis
Immunoglobulin Heavy Chains / chemistry
Immunoglobulin Heavy Chains / immunology*
Immunologic Memory
Malaria / immunology
Malaria / parasitology
Malaria / prevention & control
Malaria, Falciparum / immunology
Malaria, Falciparum / parasitology
Malaria, Falciparum / prevention & control*
Male
Mice
Models, Molecular
Plasmodium berghei / immunology
Plasmodium falciparum / immunology
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Protozoan Proteins / chemistry
Protozoan Proteins / genetics
Protozoan Proteins / immunology*
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Sporozoites / chemistry
Sporozoites / immunology

Substances

Antibodies, Protozoan
Antigens, Protozoan
Epitopes
Immunoglobulin Heavy Chains
Protozoan Proteins
Recombinant Proteins
circumsporozoite protein, Protozoan

Abstract

Publication types

MeSH terms

Substances

Grants and funding