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

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1197-1209.e10
Issue number6
StatePublished - Dec 19 2017
Externally publishedYes


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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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