title: Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium falciparum Sexual Stage Protein Pfs230.
abstract: Development of a Plasmodium falciparum (Pf) transmission blocking vaccine (TBV) has the potential to significantly impact malaria control. Antibodies elicited against sexual stage proteins in the human bloodstream are taken up with the blood meal of the mosquitoes and inactivate parasite development in the mosquito. In a phase 1 trial, a leading TBV identified as Pfs25-EPA/Alhydrogel® appeared safe and immunogenic, however, the level of Pfs25-specific antibodies were likely too low for an effective vaccine. Pfs230, a 230-kDa sexual stage protein expressed in gametocytes is an alternative vaccine candidate. A unique 6-cysteine-rich domain structure within Pfs230 have thwarted its recombinant expression and characterization for clinical evaluation for nearly a quarter of a century. Here, we report on the identification, biochemical, biophysical, and immunological characterization of recombinant Pfs230 domains. Rabbit antibodies generated against recombinant Pfs230 domains blocked mosquito transmission of a laboratory strain and two field isolates using an ex vivo assay. A planned clinical trial of the Pfs230 vaccine is a significant step toward the potential development of a transmission blocking vaccine to eliminate malaria.
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: MacDonald
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Vu
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Richard
authors.initials: R
authors.lastname: Shimp
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Karine
authors.initials: K
authors.lastname: Reiter
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Raul
authors.initials: R
authors.lastname: Herrera
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Martin
authors.initials: M
authors.lastname: Burkhardt
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Olga
authors.initials: O
authors.lastname: Muratova
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Joan
authors.initials: J
authors.lastname: Aebig
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Kelly
authors.initials: K
authors.lastname: Rausch
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Lynn
authors.initials: L
authors.lastname: Lambert
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Nikiah
authors.initials: N
authors.lastname: Dawson
authors.affiliation: the Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400 Thailand, and.
authors.forename: Jetsumon
authors.initials: J
authors.lastname: Sattabongkot
authors.affiliation: the Rosetta Design Group LLC, Burlington, Vermont 05401.
authors.forename: Xavier
authors.initials: X
authors.lastname: Ambroggio
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Laboratory of Malaria Immunology and Vaccinology, NIAID, National Institutes of Health, Rockville, Maryland 20852, dnarum@niaid.nih.gov.
authors.forename: David L
authors.initials: DL
authors.lastname: Narum
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D017780:Malaria Vaccines / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000635:transmission; D010963:Plasmodium falciparum / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D000072417:Protein Domains; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D011817:Rabbits
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; C430263:Pfs230 antigen, Plasmodium falciparum; D015800:Protozoan Proteins
keywords: Pfs230; Pichia pastoris; malaria; protein structure; recombinant protein expression; transmission blocking; vaccine; yeast