title: Transgenic parasites stably expressing full-length Plasmodium falciparum circumsporozoite protein as a model for vaccine down-selection in mice using sterile protection as an endpoint.
abstract: Circumsporozoite protein (CSP) of Plasmodium falciparum is a protective human malaria vaccine candidate. There is an urgent need for models that can rapidly down-select novel CSP-based vaccine candidates. In the present study, the mouse-mosquito transmission cycle of a transgenic Plasmodium berghei malaria parasite stably expressing a functional full-length P. falciparum CSP was optimized to consistently produce infective sporozoites for protection studies. A minimal sporozoite challenge dose was established, and protection was defined as the absence of blood-stage parasites 14 days after intravenous challenge. The specificity of protection was confirmed by vaccinating mice with multiple CSP constructs of differing lengths and compositions. Constructs that induced high NANP repeat-specific antibody titers in enzyme-linked immunosorbent assays were protective, and the degree of protection was dependent on the antigen dose. There was a positive correlation between antibody avidity and protection. The antibodies in the protected mice recognized the native CSP on the parasites and showed sporozoite invasion inhibitory activity. Passive transfer of anti-CSP antibodies into naive mice also induced protection. Thus, we have demonstrated the utility of a mouse efficacy model to down-select human CSP-based vaccine formulations.
authors.affiliation: Malaria Vaccine Development Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Porter
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nicki
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Pool
authors.forename: Margot
authors.initials: M
authors.lastname: DeBot
authors.forename: Ratish M
authors.initials: RM
authors.lastname: Illam
authors.forename: Clara
authors.initials: C
authors.lastname: Brando
authors.forename: Brooke
authors.initials: B
authors.lastname: Bozick
authors.forename: Patricia
authors.initials: P
authors.lastname: De La Vega
authors.forename: Divya
authors.initials: D
authors.lastname: Angra
authors.forename: Roberta
authors.initials: R
authors.lastname: Spaccapelo
authors.forename: Andrea
authors.initials: A
authors.lastname: Crisanti
authors.forename: Jittawadee R
authors.initials: JR
authors.lastname: Murphy
authors.forename: Jason W
authors.initials: JW
authors.lastname: Bennett
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwenk
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D009033:Culicidae; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000517:prevention & control*; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D014611:Vaccination / Q000379:methods*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan
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