Avid binding by B cells to the Plasmodium circumsporozoite protein repeat suppresses responses to protective subdominant epitopes

Cell Rep. 2021 Apr 13;35(2):108996. doi: 10.1016/j.celrep.2021.108996.


Antibodies targeting the NANP/NVDP repeat domain of the Plasmodium falciparum circumsporozoite protein (CSPRepeat) can protect against malaria. However, it has also been suggested that the CSPRepeat is a decoy that prevents the immune system from mounting responses against other domains of CSP. Here, we show that, following parasite immunization, B cell responses to the CSPRepeat are immunodominant over responses to other CSP domains despite the presence of similar numbers of naive B cells able to bind these regions. We find that this immunodominance is driven by avid binding of the CSPRepeat to cognate B cells that are able to expand at the expense of B cells with other specificities. We further show that mice immunized with repeat-truncated CSP molecules develop responses to subdominant epitopes and are protected against malaria. These data demonstrate that the CSPRepeat functions as a decoy, but truncated CSP molecules may be an approach for malaria vaccination.

Keywords: B cells; Plasmodium falciparum; circumsporozoite protein; immunodominance; immunodomination; malaria; malaria vaccines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anopheles / parasitology
  • Antibodies, Neutralizing / biosynthesis
  • Antibodies, Protozoan / biosynthesis*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / parasitology
  • Female
  • Gene Expression
  • Immunization / methods*
  • Malaria / immunology
  • Malaria / parasitology
  • Malaria / prevention & control*
  • Malaria Vaccines / administration & dosage*
  • Malaria Vaccines / biosynthesis
  • Malaria Vaccines / genetics
  • Mice
  • Mice, Inbred C57BL
  • Peptides / administration & dosage*
  • Peptides / genetics
  • Peptides / immunology
  • Plasmodium berghei / drug effects*
  • Plasmodium berghei / immunology
  • Plasmodium berghei / pathogenicity
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / immunology
  • Plasmodium falciparum / pathogenicity
  • Protein Binding
  • Protozoan Proteins / genetics*
  • Protozoan Proteins / immunology
  • Sporozoites / immunology
  • Sporozoites / radiation effects
  • Transgenes
  • Vaccines, Attenuated


  • Antibodies, Neutralizing
  • Antibodies, Protozoan
  • Malaria Vaccines
  • Peptides
  • Protozoan Proteins
  • Vaccines, Attenuated
  • circumsporozoite protein, Protozoan