title: Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice.
abstract: Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. No licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (CSP), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. We have used vectored immunoprophylaxis (VIP), an adeno-associated virus-based technology, to introduce preformed antibody genes encoding anti-P. falciparum CSP mAb into mice. VIP vector-transduced mice exhibited long-lived mAb expression at up to 1,200 µg/mL in serum, and up to 70% were protected from both i.v. and mosquito bite challenge with transgenic Plasmodium berghei rodent sporozoites that incorporate the P. falciparum target of the mAb in their CSP. Serum antibody levels and protection from mosquito bite challenge were dependent on the dose of the VIP vector. All individual mice expressing CSP-specific mAb 2A10 at 1 mg/mL or more were completely protected, suggesting that in this model system, exceeding that threshold results in consistent sterile protection. Our results demonstrate the potential of VIP as a path toward the elusive goal of immunization against malaria.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;
authors.forename: Cailin
authors.initials: C
authors.lastname: Deal
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; and.
authors.forename: Alejandro B
authors.initials: AB
authors.lastname: Balazs
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;
authors.forename: Diego A
authors.initials: DA
authors.lastname: Espinosa
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;
authors.forename: Fidel
authors.initials: F
authors.lastname: Zavala
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125.
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; gketner@jhsph.edu.
authors.forename: Gary
authors.initials: G
authors.lastname: Ketner
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000096:biosynthesis / Q000235:genetics; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000235:genetics; D000913:Antibodies, Protozoan / Q000096:biosynthesis / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000235:genetics*; D016778:Malaria, Falciparum / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D000913:Antibodies, Protozoan; D017780:Malaria Vaccines
keywords: AAV; vectored gene delivery
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