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Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs

View ORCID ProfileRajagopal Murugan, View ORCID ProfileStephen W. Scally, Giulia Costa, Ghulam Mustafa, Elaine Thai, Tizian Decker, View ORCID ProfileAlexandre Bosch, Katherine Prieto, View ORCID ProfileElena A. Levashina, View ORCID ProfileJean-Philippe Julien, View ORCID ProfileHedda Wardemann
doi: https://doi.org/10.1101/798769
Rajagopal Murugan
B Cell Immunology, German Cancer Research Institute (DKFZ), Heidelberg 69120, Germany
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  • ORCID record for Rajagopal Murugan
Stephen W. Scally
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, CanadaDepartment of Biochemistry, University of Toronto, ON M5G 0A4, CanadaDepartment of Immunology, University of Toronto, ON M5G 0A4, Canada
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Giulia Costa
Vector Biology Unit, Max Planck Institute for Infection Biology, Berlin 10117, Germany
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Ghulam Mustafa
B Cell Immunology, German Cancer Research Institute (DKFZ), Heidelberg 69120, Germany
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Elaine Thai
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, CanadaDepartment of Immunology, University of Toronto, ON M5G 0A4, Canada
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Tizian Decker
B Cell Immunology, German Cancer Research Institute (DKFZ), Heidelberg 69120, Germany
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Alexandre Bosch
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada
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  • ORCID record for Alexandre Bosch
Katherine Prieto
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada
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Elena A. Levashina
Vector Biology Unit, Max Planck Institute for Infection Biology, Berlin 10117, Germany
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  • ORCID record for Elena A. Levashina
  • For correspondence: h.wardemann@dkfz.de jean-philippe.julien@sickkids.ca levashina@mpiib-berlin.mpg.de
Jean-Philippe Julien
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, CanadaDepartment of Biochemistry, University of Toronto, ON M5G 0A4, CanadaDepartment of Immunology, University of Toronto, ON M5G 0A4, Canada
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  • For correspondence: h.wardemann@dkfz.de jean-philippe.julien@sickkids.ca levashina@mpiib-berlin.mpg.de
Hedda Wardemann
B Cell Immunology, German Cancer Research Institute (DKFZ), Heidelberg 69120, Germany
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  • For correspondence: h.wardemann@dkfz.de jean-philippe.julien@sickkids.ca levashina@mpiib-berlin.mpg.de
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SUMMARY

Circumsporozoite protein of the human malaria parasite Plasmodium falciparum (PfCSP) is the main target of antibodies that prevent the infection and disease. Protective antibodies recognize the central PfCSP domain, but our understanding of how parasite inhibition is associated with recognition of this domain and with the evolution of potent antibodies remains scattered. Here, we characterized the epitope specificity of 200 human monoclonal PfCSP antibodies. We show that the majority of PfCSP antibodies bind to NANP and NANP-like motifs with different preferences and define the molecular basis for recognition. Epitope cross-reactivity evolved with increasing antibody affinity around a conserved (N/D)P-NANP-N(V/A) core. High affinity to this motif, but not binding to NANP-like motifs, was associated with parasite inhibition and protection. Thus, NANP drives the development of potent PfCSP antibodies independently of their cross-reactivity profile, a finding with direct implications for the design of a second-generation PfCSP-based malaria vaccine.

HIGHLIGHTS

  • The majority of human PfCSP antibodies recognize multiple epitopes

  • NANP affinity maturation drives the evolution of cross-reactive PfCSP antibodies

  • Preferential PfCSP antibody binding to a conserved core motif

  • High affinity not epitope specificity is associated with PfCSP antibody potency

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 09, 2019.
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Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs
Rajagopal Murugan, Stephen W. Scally, Giulia Costa, Ghulam Mustafa, Elaine Thai, Tizian Decker, Alexandre Bosch, Katherine Prieto, Elena A. Levashina, Jean-Philippe Julien, Hedda Wardemann
bioRxiv 798769; doi: https://doi.org/10.1101/798769
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Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs
Rajagopal Murugan, Stephen W. Scally, Giulia Costa, Ghulam Mustafa, Elaine Thai, Tizian Decker, Alexandre Bosch, Katherine Prieto, Elena A. Levashina, Jean-Philippe Julien, Hedda Wardemann
bioRxiv 798769; doi: https://doi.org/10.1101/798769

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