title: Proteolytic Cleavage of the Plasmodium falciparum Circumsporozoite Protein Is a Target of Protective Antibodies.
abstract: Studies in animals and human volunteers demonstrate that antibodies against the repeat-region of the Plasmodium circumsporozoite protein (CSP) abrogate sporozoite infection. However, the realization that the N- and C- terminal regions flanking the repeats play essential roles in parasite infectivity raised the possibility that they could be targeted by protective antibodies. We characterized a monoclonal antibody (mAb5D5) specific for the N-terminus of the P. falciparum CSP, which inhibits the proteolytic cleavage of the CSP, a key requirement for parasite infection of hepatocytes. Adoptive transfer of mAb5D5 strongly inhibits the in vivo infection of sporozoites expressing the N-terminus of P. falciparum CSP, and this protection is greatly enhanced when combined with antirepeat antibodies. Our results show that antibodies interfering with molecular processes required for parasite infectivity can exert a strong in vivo protective activity and indicate that pre-erythrocytic vaccines against Plasmodium should include the CSP N-terminal region.
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Espinosa
authors.affiliation: Leidos Inc, Frederick, Maryland.
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Gutierrez
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore.
authors.forename: Maricarmen
authors.initials: M
authors.lastname: Rojas-López
authors.affiliation: Leidos Inc, Frederick, Maryland.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Noe
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore.
authors.forename: Lirong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore.
authors.forename: Sze-Wah
authors.initials: SW
authors.lastname: Tse
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore.
authors.forename: Photini
authors.initials: P
authors.lastname: Sinnis
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore.
authors.forename: Fidel
authors.initials: F
authors.lastname: Zavala
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000913:Antibodies, Protozoan / Q000276:immunology*; D000918:Antibody Specificity; D000939:Epitopes / Q000276:immunology; D005260:Female; D022781:Hepatocytes / Q000469:parasitology; D006801:Humans; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D000939:Epitopes; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan
keywords: CSP; P. falciparum; antibodies; malaria; sporozoites; vaccine