Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies

Immunity. 2021 Dec 14;54(12):2859-2876.e7. doi: 10.1016/j.immuni.2021.10.017. Epub 2021 Nov 16.


Repeat antigens, such as the Plasmodium falciparum circumsporozoite protein (PfCSP), use both sequence degeneracy and structural diversity to evade the immune response. A few PfCSP-directed antibodies have been identified that are effective at preventing malaria infection, including CIS43, but how these repeat-targeting antibodies might be improved has been unclear. Here, we engineered a humanized mouse model in which B cells expressed inferred human germline CIS43 (iGL-CIS43) B cell receptors and used both vaccination and bioinformatic analysis to obtain variant CIS43 antibodies with improved protective capacity. One such antibody, iGL-CIS43.D3, was significantly more potent than the current best-in-class PfCSP-directed antibody. We found that vaccination with a junctional epitope peptide was more effective than full-length PfCSP at recruiting iGL-CIS43 B cells to germinal centers. Structure-function analysis revealed multiple somatic hypermutations that combinatorically improved protection. This mouse model can thus be used to understand vaccine immunogens and to develop highly potent anti-malarial antibodies.

Keywords: PfCSP; adoptively transferred B cells; antibody CIS43; circumsporozoite; epitope-focused immunization; in situ vaccination; junctional epitope; malaria; passive protective.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Protozoan / metabolism
  • B-Lymphocyte Subsets / immunology*
  • Disease Models, Animal
  • Epitopes / genetics
  • Epitopes / immunology*
  • Genetic Engineering
  • Humans
  • Immune Evasion
  • Immunogenicity, Vaccine
  • Malaria / immunology*
  • Malaria Vaccines / immunology*
  • Mice
  • Mice, SCID
  • Plasmodium falciparum / physiology*
  • Protozoan Proteins / genetics
  • Protozoan Proteins / immunology*
  • Structure-Activity Relationship
  • Vaccination
  • Vaccines, DNA / immunology*


  • Antibodies, Protozoan
  • Epitopes
  • Malaria Vaccines
  • PfCSP DNA vaccine
  • Protozoan Proteins
  • Vaccines, DNA
  • circumsporozoite protein, Protozoan