title: Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects.
abstract: Immunization of humans with whole sporozoites confers complete, sterilizing immunity against malaria infection. However, achieving consistent safety while maintaining immunogenicity of whole parasite vaccines remains a formidable challenge. We generated a genetically attenuated Plasmodium falciparum (Pf) malaria parasite by deleting three genes expressed in the pre-erythrocytic stage (Pf p52-/p36-/sap1-). We then tested the safety and immunogenicity of the genetically engineered (Pf GAP3KO) sporozoites in human volunteers. Pf GAP3KO sporozoites were delivered to 10 volunteers using infected mosquito bites with a single exposure consisting of 150 to 200 bites per subject. All subjects remained blood stage-negative and developed inhibitory antibodies to sporozoites. GAP3KO rodent malaria parasites engendered complete, protracted immunity against infectious sporozoite challenge in mice. The results warrant further clinical testing of Pf GAP3KO and its potential development into a vaccine strain.
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA. stefan.kappe@cidresearch.org jkublin@fredhutch.org.|Department of Global Health, University of Washington, Seattle, WA 98195, USA.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Kublin
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Mikolajczak
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Sack
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Matt E
authors.initials: ME
authors.lastname: Fishbaugher
authors.affiliation: Department of Laboratory Medicine, University of Washington, 1959 Northeast Pacific Street, NW150, Seattle, WA 98195-7110, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Seilie
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Shelton
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Tracie
authors.initials: T
authors.lastname: VonGoedert
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Melike
authors.initials: M
authors.lastname: Firat
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Magee
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Fritzen
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Will
authors.initials: W
authors.lastname: Betz
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Heather S
authors.initials: HS
authors.lastname: Kain
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Dorender A
authors.initials: DA
authors.lastname: Dankwa
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Ryan W J
authors.initials: RW
authors.lastname: Steel
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Vaughan
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: D
authors.initials: D
authors.lastname: Noah Sather
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.|Department of Laboratory Medicine, University of Washington, 1959 Northeast Pacific Street, NW150, Seattle, WA 98195-7110, USA.|Center for Emerging and Re-emerging Infectious Diseases and Department of Microbiology, University of Washington, 750 Republican Street, E630, Seattle, WA 98109, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Murphy
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA. stefan.kappe@cidresearch.org jkublin@fredhutch.org.|Department of Global Health, University of Washington, Seattle, WA 98195, USA.
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
mesh_terms: D000328:Adult; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D005260:Female; D017353:Gene Deletion; D005818:Genetic Engineering; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology; D015800:Protozoan Proteins / Q000235:genetics; D034101:Sporozoites / Q000235:genetics* / Q000276:immunology; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D000913:Antibodies, Protozoan; D007074:Immunoglobulin G; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014613:Vaccines, Attenuated